Roslin response to UK Government consultation on gene editing

Introduction

1  Please provide your consent to participate in this consultation.

I consent to participate.

2  Would you like your response to remain confidential?

No

If you answered yes to this question, please give your reason.:

3  What is your name?

Full Name: The Roslin Institute

4  What is your email address?

Email: helen.sang@roslin.ed.ac.uk

5  Please tell us who you are responding as?

Academia - In an official capacity as a representative of an academic institution. 

About Your Business / Organisation 

7  What is the name of your business/organisation?

Please state: The Roslin Institute, University of Edinburgh

8  Which of the following areas are you interested in? 

Breeding farmed animals, Human and veterinary medicines, Other sectors/activities

9  Where does your business/organisation operate? 

Please state: UK and internationally

Part 1: The regulation of GMOs which could have been developed using traditional breeding methods

10  Currently, organisms developed using genetic technologies such as GE are regulated as genetically modified organisms (GMOs) even if their genetic change(s) could have been produced through traditional breeding. Do you agree with this?

No – they should not continue to be regulated a GMO

Please explain your answer, providing specific evidence where appropriate. This may include suggestions for an alternative regulatory approach.:

Genetic variation is the presence of differences in the sequences of genomes between individual organisms of a species. There is substantial genetic variation in all populations of farmed animals and crops. This variation either existed in the ancestral populations from which our familiar farmed animals and crops have been domesticated, or has arisen due to mutation. Selective breeding has utilised this genetic variation over centuries by choosing the best parents for mating/crossing, and this has resulted in substantial improvements in the productivity of farmed animals and crops. In addition, people have utilised a wide range of technologies to introduce genetic variation into crops and farmed animals, including introgression (the movement of a gene variant from one breed/species into the gene pool of another by the repeated backcrossing of a hybrid with one of its parent breed/species) and mutagenesis using chemicals or radiation (in some crop species).  In recent decades, the technologies of genetic modification and gene editing have been introduced as methods to make specific genetic changes. These new technologies have advantages in their specificity and reduced potential for unplanned negative effects. Breeding technologies that have been in use for many years are not regulated while newer technologies are heavily regulated, even though this may not reflect the potential of a technology for causing unknown effects. For example, selective breeding is essentially unregulated, although it is rarely applied to achieve a specific genetic change and has a degree of randomness that can result in profound changes to plant and animal phenotypes (e.g. https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007759,https://www.pnas.org/content/94/23/12457). Similarly, random mutagenesis in plant breeding is lightly regulated compared to GMOs, yet is not targeted in any way and has potential for unintended effects, not associated with the primary breeding goals. Introgression of targeted genetic variation from one breed or related species to another is achieved by backcrossing for several generations, which is a lengthy and laborious process, and can result in unfavourable or unintended effects due to the action of linked variants in the flanking regions of the target variant in the genome.

The “traditional” technologies associated with breeding of farmed animals and crops and the newer genetic technologies have made substantial contributions to the supply and quality of food for mankind. The challenges of climate change and achieving adequate nutrition for healthy populations require the bringing together of all approaches to meet the global demand for a healthy diet while significantly reducing the impacts of agriculture on the environment. Genetic technologies have important contributions to make to meeting these challenges.

• Gene editing is a significant advance in genome engineering technologies that utilises a suite of new molecular tools that enable very specific genetic changes to be introduced into a genome. These genome edits alter the genetic material already present in that organism or species, and may be designed to introduce anything from very small genetic mutations or larger DNA rearrangements, to introducing new genetic material. Innate inaccuracies in DNA replication and genetic recombination (that occurs during the production of gametes) can result in changes including single nucleotide changes, small insertions or deletions of a few nucleotides, and larger deletions and rearrangements of DNA sequences, via mechanisms that are involved in genetic changes introduced via genome editing. Any of these can alter genes in ways that alter the protein encoded by a gene, or completely inactivate expression of the gene. Gene editing is a precise technology in which specific genetic changes can be made.
• Genome editing can therefore be used to generate and utilise genetic variation in farmed organisms in a substantially more precise and controlled manner than several existing and accepted breeding techniques. For example, it is possible to perform targeted introgression of favourable variants across breeds, lines and related species to benefit production, health and welfare. This is achieved without the negative effects associated with genetically linked variants (so called ‘linkage drag’). Furthermore, rather than relying on the imprecise approach of the random mutagenesis permitted in crop breeding, it is possible to make targeted changes to genomic locations known to be associated with valuable genetic traits. This is more efficient: genetic improvement can be achieved in a single generation, substantially reduces the chances of negative impacts of randomly induced mutations and can reduce by many years/generations the time taken to introduce a beneficial genetic change.
• After either genetic modification or gene editing, it is possible using standard research techniques (e.g. whole genome resequencing, targeted sequencing) to scan the genome of the resulting animal or plant for unplanned additional genetic changes, and assess their potential risk. The technology can introduce additional unintended sequence changes in the genome (off-target effects), though these are themselves a type of random mutation of the same kind that occurs spontaneously in each generation. It should be noted that the vast majority of off-target effects, if they do occur, are likely to have no impact on any trait in the organisms, either negative or positive. The vast majority will be neutral, as is the case for spontaneously-occurring mutations. Breeding programmes are structured to select for desired genetic characteristics over generations so any off-target mutations will be effectively lost during this process as they will not be included in positive selection.
• Regulation of gene editing should involve a risk – benefit assessment of the environmental/health/welfare outcomes of the genetic alteration (both positive and potential risks) and a system of regulation be developed to reflect different levels of risk.

11  Do organisms produced by GE or other genetic technologies pose a similar, lesser or greater risk of harm to human health or the environment compared with their traditionally bred counterparts as a result of how they were produced?

Similar

Please provide evidence to support your response including details of the genetic technology, the specific risks and why they do or do not differ. Please also state which applications/areas your answer relates to (for example: does it apply to the cultivation of crop plants, breeding of farmed animals, human food, animal feed, human and veterinary medicines, other applications/ areas). :

• The outcome of the application of any genetic technologies for a specific purpose relate to the purpose/outcome, not the technology used to make the genetic change.
• Novel phenotypes can be generated that could not be produced by established breeding methods, such as resistance to an infectious disease in animals. This has the potential to reduce associated risks to humans due to the reduced use of antibiotics/antivirals (and therefore helping to tackle antimicrobial resistance), the improved efficiency of production with positive impacts on the environment (through reduced land use for example), improved animal health and welfare, and potentially reduced risk of zoonoses and the associated risk of human epidemics of infectious disease.
• All methods for introducing genetic changes to animals and plants, including gene editing but also including selective breeding and mutagenesis, can introduce profound changes to form and function (phenotype) . They may also introduce relatively minor phenotypic changes. These changes to the phenotype of an animal or crop may or may not be associated with an identifiable risk, whether or not are not present in the original animal or plant. The risk of any specific genetic alteration therefore requires a fit-for-purpose risk assessment and regulatory system.
• The technology itself is not riskier than genetic breeding and selection for novel phenotypes. The genome editing molecules typically act early in the development of an animal, and result in a specific targeted change. In generation of gene-edited animals there is no longterm persistence of the molecules used to generate the edit, the only remaining genetic change being the edit itself.
• In animal breeding, gene editing facilitates introduction of very specific genetic changes that can be validated by sequencing of the altered gene. The welfare of farmed animals is currently regulated during the generation of experimental gene edited animals by the Animal (Scientific Procedures) Act 1986 and the welfare of production of animals is regulated via the Animal Welfare Act 2006 (and subsequent legislation). The genomes of edited animals can be scanned for unknown or off-target effects, but interpretation of this information may be difficult as it is well-established that novel mutations occur every generation during traditional breeding and in the development of an animal.
• An example of the use of gene editing to introduce a valuable trait that cannot be achieved effectively by established breeding strategies is the use of gene editing to modify a gene in pigs that results in resistance to a major disease which is endemic in the UK https://www.ed.ac.uk/roslin/facilities-resources/larif/case-studies/industry-partners. The FAO estimates PRRS causes 20% fatality in affected pig herds  (http://www.fao.org/3/a-al849e.pdf)and higher mortalities have been reported (https://pubmed.ncbi.nlm.nih.gov/9481519/). While selective breeding could make incremental improvements to PRRS resistance over many generations, the use of this example of a single edit at a precise location in the pig genome demonstrates that complete resistance to a major disease can be achieved in a single generation. Researchers globally are developing gene editing approaches to produce animals that are resistant to devastating diseases (e.g. https://www.pnas.org/content/117/4/2108 https://pubmed.ncbi.nlm.nih.gov/31159925/): these animals have the potential to be of major economic benefit, improve animal welfare by effectively reducing disease burden on farmed animals, and reduce the use of antibiotics/antivirals in the food chain.

12  Are there any non-safety issues to consider (e.g. impacts on trade, consumer choice, intellectual property, regulatory, animal welfare or others), if organisms produced by GE or other genetic technologies, which could have been produced naturally or through traditional breeding methods, were not regulated as GMOs?

Yes

Please provide evidence to support your response and expand on what these non-safety issues are.:

• For the UK to remain competitive in food production in an international marketplace it requires the ability to innovate in the use of technology to improve production and welfare, and to develop an appropriate regulatory framework to ensure the country can benefit from the innovation in a timely manner. Failure to achieve this would mean that the UK would be at a competitive disadvantage compared to other major agriculture and aquaculture countries globally.
• The products may not be accepted by some trading partners. In the case of animal breeding the supply of genetics (animals for breeding) is mostly carried out by international companies that may have to differentiate products for different markets.
• Food products from GE animals and crops may not be accepted by some countries. It should be noted that the regulations are in debate in many countries and these barriers may become less.
• There may be positive animal welfare impacts, for example in conferring resistance to major diseases of farmed animals, and the potential for gene edited animals to avoid practices such as de-horning (https://pubmed.ncbi.nlm.nih.gov/27153274/ ) or castration (reviewed in
• https://genomebiology.biomedcentral.com/articles/10.1186/s13059-018-1583-1). There may be also be unintended negative animal welfare impacts but these will be identified at the research stage of developing the specific gene edit and not introduced into breeding animals. Such unintended negative impacts can occur with other breeding technologies such as introgression and mutagenesis.
• Consumers may express a preference for or against gene edited food products, depending on the balance of benefits provided by the gene edit involved. Retailers may express a preference for or against gene edited food products, which is likely to be driven by perceived consumer preference.
• It may be difficult to identify which organisms, or their derivative products, have had gene editing performed at some generation in their ancestry, if these were edited to carry genetic variants already in existence. Thus detection and enforcement of restrictions on organisms and products may in some cases be difficult.

13  What criteria should be used to determine whether an organism produced by gene editing or another genetic technology, could have been produced by traditional breeding or not?

Please provide evidence to support your response.:

• Standard mating/crossing and breeding can result in selection of small genetic changes (mutations) that occur spontaneously every generation (estimated ~ 30 mutations per generation in mammals) or major changes to the genome, such as large duplications, deletions and translocations, via processes such as the imperfect nature of DNA replication and repair, and DNA recombination. Such changes, which occur spontaneously, are unregulated, and currently are not identified by any regulatory process involved in approving products for food. Therefore, it is exceptionally challenging to define which changes to the genome could have been produced by ‘traditional’ breeding. Most changes introduced by genome editing, providing it does not result in the incorporation of genetic material from another organism (which would be equivalent to a GMO), could theoretically occur by traditional breeding. The addition of entirely distinct DNA sequence not previously present in the genome of that species, however, could not have been produced through traditional breeding and is detectable using suitable methods.
• The smallest genetic changes, generated by any technology or selected during breeding, can result in profound changes to a phenotype, and as such the risk of any specific genetic alteration requires a fit-for-purpose risk assessment and regulatory system. Defining the level of regulation based on the size of the change is therefore not logical, and attention must be placed on the phenotypic consequences of the edit made to the genome. We recommend that the technology that is used is not the focus of the regulatory process, rather that criteria are defined that are based on an appropriate risk assessment of the outcomes, because our view is that there are no risks in the application of genetic technologies per se.

Part 2: Questions on broad reform of legislation governing organisms produced using genetic technologies

14  There are a number of existing, non-GM regulations that control the use of organisms and/or products derived from them. The GMO legislation applies additional controls when the organism or product has been developed using particular technologies.Do you think existing, non-GM legislation is sufficient to deal with all organisms irrespective of the way that they were produced or is additional legislation needed? Please indicate in the table whether, yes, the existing non-GMO legislation is sufficient, or no, existing non-GMO legislation is insufficient and additional governance measures (regulatory or non-regulatory) are needed.Please answer Y/N for each of the following sectors/activities:

Gov_Sufficiency - Yes (sufficient governance):

Gov_Sufficiency - No (insufficient governance):

Breeding farmed animals

Please provide evidence to support your response.:

We only comment on 5b where our expertise lies. From a scientific perspective we think that a system of risk assessment of the predicted biological effects (on individual animals, production systems and any environmental consequences) and possibly some established standard of screening for off-target effects is required. It will be challenging to regulate the introduction of many GE alterations as some changes will be indistinguishable from the genetic variation present in a species. We do however recognise that there is an expectation in the UK (and other countries) that GMO-derived foods be labelled as such. There needs to be debate and consultation about whether GE food products are expected to be labelled as such (if so they need to be licensed by regulations of some form). This should be accompanied by development of more effective ways to engage the wider public in reviewing the risks and benefits of the application of genome editing technologies to inform development of appropriate regulatory systems.

15  Where you have answered no (existing, non-GMO legislation is insufficient to deal with organisms produced by genetic technologies), please describe what additional regulatory or non-regulatory measures you think are required to address this insufficiency, including any changes you think need to be made to existing non-GMO legislation. Please explain how any additional measures you identify should be triggered (for example: novelty, risk, other factors).

Please provide evidence to support your response.:

Genetic technologies applied in animal breeding have specific aspects of concern to the public, mainly in terms of animal welfare. The current regulations apply to welfare of farmed animals in farming systems, rather than regulation of breeds themselves. The effectiveness of current regulations should be assessed and specific aspects relating to application of genetic technologies considered, to assess if the current regulations are effective in their scope.