Transcript Regulatory Paradigms for Modern Breeding

Regulatory Paradigms
for
Modern Breeding
Drew L. Kershen
Earl Sneed Centennial Prof. Emeritus
NABC-26 at Cornell University
October 9, 2014
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
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
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.”
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.”
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.”
United States Law
USDA-APHIS
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Plant Protection Act
– Regulated Article – any organism altered or produced through genetic engineering
– Plant Pest
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Regulated Letters of Inquiry
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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
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Not regulated articles – Knockout effect
– No Letters of Inquiry on TALENs or CRISPRs
– Two Letters on Synthetic Biology: BioGlow for glowing plants – not regulated
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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
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
United States Law
Food & Drug Agency (FDA)
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Federal Food, Drug & Cosmetic Act (FFDCA),
– Food
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“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
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Safe and Efficacious; Pre-market approval; clinical tests
Ventria Rehydration Solution (produced in rice)
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FDA did not respond; Ventria withdrew application – disagreement about GRAS status or drug status
– Animal Drug
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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
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Decisions in a timely fashion
Tiered risk analysis – not all GE animals pose a novel risk
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TALENS transfer of “polled” trait from Angus (beef) to Holsteins (dairy)
GRAS status, like food, should apply to identified low risk categories
European Union Law
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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
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
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
Alphabetical List
Sources
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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.thescientist.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, 10:29432974
Eriksson, D. et al., (August 2014) The slippery slope of cisgenesis, Nat. Biotech. 32:727
(correspondence)
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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)
Alphabetical List
Sources
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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.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.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)
Alphabetical List
Sources
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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)
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
Alphabetical List
Sources
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Sustainability Council of New Zealand Trust against The Environmental Protection Authority, CIV 2013-485877, 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
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US-APHIS, Regulated Letters of Inquiry at http://www.aphis.usda.gov (viewed September 4, 2014)
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
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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/
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IAP Statement on Realising Global Potential in Synthetic Biology: Scientific Opportunities and Good Governance (7 May
2014)
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.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
Thank you
Drew L. Kershen
300 W. Timberdell Road
Norman, OK 73019-5081
[email protected]
(405) 325-4784