1. Food derived using new technologies: lessons learned from GM food safety assessment
Janet Gorst on behalf of Lisa Kelly
Risk Assessment – Biological Sciences

2. Outline
Overview of GM food safety assessment
Emergence of new technologies/new breeding techniques for modifying genomes
The current problem and the FSANZ review
Genome editing as an example of issues and questions

3. Standard 1.5.2 – Food produced using gene technology
Establishes a pre-market assessment and approval system for GM foods & imposes mandatory food labelling requirements

4. Key definitions
food produced using gene technology means a food which has been derived or developed from an organism which has been modified by gene technology gene technology means recombinant DNA techniques that alter the heritable genetic material of living cells or organisms

5. No presumption of safety, formal risk assessment applied
Current food regulation is based on process
Conventional foods have presumption of safety based on history of safe use
Conventional breeding
Traditional cross breeding & selection
Mutation breeding (plants)
Cell culture techniques
Gene Technology
Recombinant DNA techniques
Transgenesis
No presumption of safety, formal risk assessment applied
No pre-market approval
Pre-market approval

6. GM food: main health & safety concerns
Expression or production of new substances as a consequence of the genetic modification
new proteins
new non-protein substances (e.g. interfering RNAs, novel herbicide metabolites)
Unintended changes arising from the insertion of new genetic material in the genome (insertional mutagenesis)
Significant (intended) changes to the nutrient composition of foods

7. GM food safety assessment
FSANZ approach consistent with Codex Principles and Guidelines
Guideline for the Conduct of Food Safety Assessment of Foods Derived from Recombinant-DNA Plants (CAC/GL )

8. Safety assessment approach

9. Key elements

10. Safety assessment outcomes
FSANZ has assessed more than 70 GM foods
Extensive experience and familiarity with foods derived from GM crops
A large evidence-base exists
No differences have been identified that raise any legitimate food safety concerns
Initial (primarily theoretical) concerns about safety particularly in relation to unintended changes are so far unfounded

11. Outline
Overview of GM food safety assessment
Emergence of new technologies/new breeding techniques for modifying genomes
The current problem and the FSANZ review
Genome editing as an example of issues and questions

12. Emergence of new breeding techniques
When the standard for GM foods was first developed, definitions were designed to essentially capture a single technique
transgenesis, where (foreign/new) DNA from another species is inserted
The new techniques are a game changer - many do not conform to the transgenesis or “GM” stereotype

13. Examples Genome editing
Site-directed nucleases (ZFN, TALENS, CRISPR/Cas9)
Oligo-directed mutagenesis
Cisgenesis/Intragenesis
GM Rootstock Grafting
Agro-infiltration (including non-germline and germline tissue)
Transient transgenics
Accelerated breeding following early flowering
Reverse Breeding
Hybrid Seed Production Technology (SPT)

14. Outline
Overview of GM food safety assessment
Emergence of new technologies/new breeding techniques for modifying genomes
The current problem and the FSANZ review
Genome editing as an example of issues and questions

15. The problem
Many of the newer techniques do not fit neatly into the current definitions for gene technology
Generates uncertainty about whether foods derived from these techniques currently come within the scope of the GM food standard
Because of their similarity to conventionally-bred foods, there is debate about whether foods derived using genome editing (in particular) should be subject to pre-market approval
Some argue the risk from these foods is no different to that of conventionally-bred foods, therefore pre-market scrutiny is not warranted

16. FSANZ Review FSANZ commenced a review in June 2017 to consider
FSANZ commenced a review in June 2017 to consider
the extent to which food derived from various NBTs should be captured for pre-market approval under Standard 1.5.2, and
whether the definitions for ‘food produced using gene technology’ and ‘gene technology’ should be changed to improve clarity about which foods require pre-market approval
An Expert Advisory Group on New Breeding Techniques (EAG NBT) has been established to assist with the review
There is no intent to review any other aspect of the standard or our approach to foods unambiguously captured by the standard

17. Review Process First Meeting with EAG  Second meeting with EAG
Targeted consultation with key stakeholders
Second meeting with EAG
Public consultation on issues paper
Final review report
Aug – Oct 17
Early 2018
Jun 17
Dec 17
Jun 18

18. Outline
Overview of GM food safety assessment
Emergence of new technologies/new breeding techniques for modifying genomes
The current problem and the FSANZ review
Genome editing as an example of issues and questions

19. Genome editing
Most attention in the debate has focused on the genome editing techniques
These techniques can be applied in a variety of ways to produce different types of outcomes
Some derived food products may be similar to, or indistinguishable from, those that may be produced through conventional breeding
There are two main approaches to facilitate genome editing
- Use of site-directed nucleases
- Oligonucleotide-directed mutagenesis

20. Site directed nucleases (SDNs) – 3 classes
There are two key components to each SDN:
A DNA recognition code (protein-based or RNA) that finds a specific site in the genome
A nuclease (protein) that cuts the double stranded DNA at that specific site
These components can be added to the host :
directly as the proteins or RNA
via a transgenic step
If by transgenesis, once the component genes have done their job, the idea is that they are segregated away during subsequent breeding

21. Site directed nucleases (SDNs)
There are three ways in which each SDN technique can be used

22. Genome editing
Most attention in the debate has focused on the genome editing techniques
These techniques can be applied in a variety of ways to produce different types of outcomes
Some derived food products may be similar to, or indistinguishable from, those that may be produced through conventional breeding
There are two main approaches to facilitate genome editing
- Use of site-directed nucleases
- Oligonucleotide-directed mutagenesis

23. Oligonucleotide-directed mutagenesis (ODM)
The chemically synthesised oligonucleotide (20 – 100 bp) has homology with the target gene except for the nucleotide(s) to be changed.
Oligonucleotide
Mismatch
oligonucleotides are added directly and hence do not involve a transgenic stage
oligonucleotides themselves are not “heritable material“
oligonucleotides act like a mutagen, but are sequence specific
- the obtained mutations cannot be distinguished from spontaneous mutations (natural variation) or mutations induced by classical mutagenesis
Modified from Songstad et al (2017) Critical Reviews in Plant Sciences

24. Changes from genome editing
mainly achieved using site-directed nuclease techniques
equivalent to transgenesis - food from transgenic organisms already subject to pre-market assessment and approval
may involve stable insertion of the nuclease gene which would be segregated away in final breeding steps (null segregant) – no new DNA or proteins in final food producing line
safety concerns would primarily arise from expression of new proteins or other substances in a food (potential allergenicity/toxicity), but also potential for off-targeting/unintended changes
DNA insertions
safety concerns would primarily arise from potential for off-targeting/unintended changes
Deletions
small nucleotide changes typically but could be more extensive
can be achieved using site-directed nuclease techniques as well as oligo-directed mutagenesis
oligo-directed mutagenesis does not involve a gene insertion step
safety concerns would primarily arise from altered protein structure/function, altered expression of existing gene products, as well as potential for off-targeting/unintended effects
Nucleotide changes

25. Questions generated by genome editing
Do all food products derived from genome edited organisms warrant pre-market assessment and approval?
What have we learned from 20 years of GM food safety assessment, and can this be applied to the current problem?
Can the presumption of safety applied to conventional foods also be applied to foods from genome edited organisms?
How do the genome-editing changes compare to those arising from conventional methods?
Are off-target effects different (nature and frequency)?

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