Download Responsible Oversight Strategies for Genome - NAS

Responsible Oversight
Strategies for Genome Editing
Technology in Agricultural
Animals in the United States
Bhanu Telugu DVM.PHD
Susan Harper, DVM (USDA-ARS)
Diane Wray-Cahen PHD (USDA-FAS)
Overview
• Introduction and Rationale for performing
genome editing
• Discuss current Regulatory landscape
• Provide a case study
Animal Biotechnologies in Context
S
C
I
E
N
T
I
F
I
C
C
O
N
T
I
N
U
U
M
Genetic Modification
Objective
▪ Mass selection
▪ Pedigree selection
▪ Marker‐assisted selection
▪ Transgenics (1980s)
(GE Animals)
▪ Genome‐wide selection
▪ Gene Editing (2000s) “Precision Breeding”
Change Genetic Makeup
Rationale for genome editing in
livestock for agricultural
applications
Current strategySelective breeding is not pragmatic
Genetic bottleneck associated with
conventional breeding
Haplotypes
A
B
: Desired allele;
: Desired QTN;
Haplotypes
A
B
:Undesired allele
:Undesired QTN
Rational Selection via Genome editing
to accelerate genetic selection
Deletion
(NHEJ)
T
G
Replacement
(HDR)
: Desirable allele;
: Desirable QTN;
:Undesirable allele
:Undesirable QTN
Rationale for Genome editing over
Conventional Breeding
Genome editing:
1. Gene deletion (knockout)
2. Gene modification
3. insertion (knockin)
Rationale:
– Overcome otherwise low heritability
– Separate “linked” genes
– Increase precision and efficiency of introducing desirable
traits (conventional breeding is random)
– Introduction of traits not available via conventional
breeding
Rationale for Genome editing
Gene deletion- knockouts
CRISPR/cas9
+ sgRNA mRNA
All piglets edited!!
Genome Editing
Potential Benefits
• Facilitates precise modifications
• Faster, more reliable, and cheaper than
conventional breeding (long generation interval)
to modify base pairs of genes
Potential Risks
• Off-target edits
• Reducing genetic diversity in genome edited
herds
• Potential spread of edited genetic material into
non-target or closely related populations (biocontainment)- issue with some than others
Additional Legal and Ethical Concerns
• Perceived novel environmental risks (Potential benefit‐
Enviropigs; Potential risks?)
• Misuse of technology for entertainment purposes and potentially nefarious reasons (Eg.,micropigs as pets in China; HOW IS DIFFERENT FROM DESIGNER DOG BREEDING)
• Application of technology developed in animals to human germline editing (NOTE: not somatic editing)
How to Regulate Genome Edited Animals ?
Mid‐1980’s  expression of need for establishment of regulatory oversight in light of the transgenic animals that have been generated
Regulation of Biotechnology in the
United States
Regulation Under the Coordinated Framework
USDA
Safe for the animal,
agriculture
and the environment
FDA
Safe for use
in food and feed
EPA
Safe for
environment
Coordinated Framework – General Principles
Federal Role in the Safe Use of Biotechnology
• USDA does not regulate GE animals for Food production. It is
the role of FDA [FDA has emerged as a de facto enforcer].
• The risks of genetically engineered (GE) organisms are not
fundamentally different from the risks posed by non-GE
organisms with similar traits.
• The existing laws provide adequate authority.
• Regulation should be science-based and conducted on a caseby-case basis (Need to be revisited for Editing animals).
How are GE animals
regulated in United States?
Transgenic animals that have recombinant
DNA (trigger) have clear guidelines
• In 2009, the Food and Drug Administration (FDA) issued Guidance: Regulation of Genetically Engineered Animals Containing Heritable Recombinant DNA Constructs
• The FDA regulates the recombinant DNA construct as a “new animal drug”, “an article intended to alter the structure or function” of the animal (trigger)
• New animal drug approval is based on a showing that the product is “safe” (for animals, humans, and the environment) and “effective” for the intended use
APHIS
FDA
FDA
Commercialization of Animal
Biotechnology
Transgenic models (mice, rats, zebrafish) GloFish (2003) [Enforcement Discretion]
Atryn Goat (2009, USA)
Project on hold
X
Oxitec mosquito (2014, Brazil)
Enviropig (Canada)
Finally approved
Commercialization ?
AquAdvantage Salmon (USA)
How to regulate edited animals that
do not have recombinant DNA
(trigger), or that are similar to
naturally occurring sequences?
Existing Regulatory Frameworks
• Many provisions intended for the regulation of conventional transgenic animals do not necessarily directly apply to animals produced through genome editing technologies.
• Regulations are already in place to protect the welfare and safety of animals, workers, the environment, and the public.
• Local oversight of genetic research involving animals includes:
• Institutional Animal Care and Use Committee (IACUC)
• Institutional Biosafety Committee (IBC)
Institutional Animal Care and Use
Committee (IACUC)
• Required by:
• Animal Welfare Act Regulations (AWAR) when regulated species are used for research, testing, or teaching
• PHS Policy when PHS funding is received
• NRC Guide for the Care and Use of Laboratory Animals and FASS Ag Guide • Establishes local oversight of the welfare and safety of animals used for research, teaching, and/or testing
• Incorporates a harm‐benefit analysis to ensure the use of animals is justified • USDA‐APHIS Animal Care Policy No. 10 requires facilities that produce cloned animals for regulated purposes to be licensed, and those that produce novel genetically engineered animals to be registered as research facilities.
• AWAR exempts agricultural animals used in food and fiber research and federal research programs.
Institutional Biosafety Committee
(IBC)
• NIH Guidelines requirement for institutions that receive NIH funding
• Establishes local oversight for research involving recombinant or synthetic nucleic acid molecules
• NIH Guidelines requirements for transgenic animals include:
• Identification and disposal guidance for animals larger than traditional laboratory animals (e.g., cattle, swine, sheep, goats, horses, and poultry)
• Permanent marking of genetically engineered offspring within 72 hours of birth, if their size permits
• Distinct and biochemically assayable DNA sequences that permit transgenics to be identified from non‐transgenic animals
• Containment and confinement practices
Miscellaneous Regulations
• Clean Water Act (33 USC 1251) with respect to contaminated runoff from animal production facilities
• Occupational Safety and Health Administration (OSHA) workplace requirements
• CDC‐NIH “Biosafety in Microbiological and Biomedical Laboratories” (BMBL) laboratory safety requirements
• State and Local Regulations related to environmental protection and worker safety
• Relevant International Standards
Regulatory framework adapted at
ARS, USDA for an editing project
• Goal is to produce pigs that do not serve as a reservoir for influenza.
• Foundation pigs will be used to produce offspring.
• Influenza challenge studies will be performed in offspring, requiring ABSL‐3 containment.
• Animals will be monitored for adverse genotypic and phenotypic stability, as well as unintended or adverse characteristics.
Regulatory framework adapted at
ARS, USDA for an editing project
• Project has been reviewed by IACUC and IBC at the University and two ARS locations.
• Review process emphasized potential animal welfare implications, biosecurity concerns, laboratory safety, potential occupational health issues, and containment/confinement practices.
• Agreements were established to clarify specific institutional responsibilities, animal ownership, and oversight roles.
• No gaps perceived in current local and government oversight processes.
Acknowledgements
Funding Sources
For More Information
“Unified” website for U.S. Regulatory Agencies
under the Coordinated Framework:
http://usbiotechreg.epa.gov/usbiotechreg/
USDA-APHIS-BRS:
http://www.aphis.usda.gov/biotechnology/index.shtml
EPA:
http://www.epa.gov/pesticides/biopesticides/pips/index.htm
FDA-CFSAN:
http://www.fda.gov/Food/Biotechnology/default.htm