THIRD WORLD NETWORK BIOSAFETY INFORMATION SERVICE
Dear Friends and Colleagues
Why Gene-Edited Organisms Must Undergo Mandatory Risk Assessment and Ethical Oversight
An overview of the differences between genome editing of plants with CRISPR/Cas nucleases classified as ‘site directed nucleases’ SDN-1 and SDN -2 applications and conventional breeding concludes that, in general, higher precision in changing the genome does not necessarily result in greater safety or higher success rates in plant breeding. The authors stress that the pattern of intended and unintended changes and the resulting new combinations of genetic information arising from genome editing will, in most cases, be different in comparison to those derived from conventional breeding. These differences co-occur with biological characteristics and risks that need to be fully investigated before any conclusions on the safety of the new organisms can be drawn.
The authors identify the following aspects as particularly important for regulatory decision-making: (1) New patterns of genetic change and resulting genetic combinations are, in many cases, likely to result from the application of SDN-1 and SDN-2; (2) The applications of ‘old’ methods of genetic engineering used in most cases to introduce the CRISPR/Cas component into the plant cells can cause a broad range of unintended effects; and (3) CRISPR/Cas technology itself can cause many specific unintended effects which go far beyond what is discussed as ‘off-target effects’.
The report highlights selected examples to provide a greater understanding of regulatory challenges resulting from SDN-1 and SDN-2 applications. These examples include changes in the composition of plants that may impact the food web or plant communication and interaction with the environment. Organisms generated by SDN-1 or SDN-2 showing enhanced fitness should undergo detailed environmental risk assessment, especially in regard to gene flow and next generation effects, as should those that are able to persist and propagate. In the latter case, measures to prevent uncontrolled spread must be put in place.
The authors conclude that the radical implications of gene editing for our species and our planet not only deserve strict regulatory oversight and mandatory risk assessment, but also deserve a broad sociological debate on the ethical implications, including nature protection and the rights of future generations. Further major ethical issues relate to animal welfare and protection as SDN-1 and SDN-2 and also SDN-3 applications that can be used on farm animals in order to produce more meat, milk with changed composition, hornless cows, virus-resistant pigs and animals that are adapted to climate change.
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Third World Network
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OVERVIEW OF GENOME EDITING APPLICATIONS USING SDN-1 AND SDN-2 IN REGARD TO EU REGULATORY ISSUES
New methods of genetic engineering (genome editing) and their potential impact on nature protection and the environment
Katharina Kawall, Juliana Miyazaki, Andreas Bauer-Panskus, Christoph Then
Testbiotech
March 2020
https://www.testbiotech.org/sites/default/files/Testbiotech_risk%20%26%20regulation%20of%20%27New%20Genomic%20Techniques%27.pdf
Summary
This report provides overview on possible impacts that new methods of genetic engineering (genome editing) can have on the environment. It is primarily concerned with CRISPR/Cas nucleases classified as ‘site directed nucleases’ SDN-1 and SDN -2. These applications are not meant to introduce additional gene sequences. The authors give an overview of the differences between the genome editing of plants with SDN-1 and SDN-2 applications and conventional breeding which are of relevance in the discussion about the regulatory decision-making process:
- In the case of conventional breeding, the first step always requires a high degree of genetic diversity that subsequently provides the basis for further crossing and selection. Conventional breeding (including ‘random’ mutagenesis) can generate biological traits which are desired, complex, distinct and heritable, often based on so-called Quantitative Trait Loci (QTLs) that are, in many cases, not well-defined at the genomic level. Due to the methods used in conventional breeding, some genetic alterations are more frequently observed than others. Inherent natural inheritance mechanisms such as the distance between two genes on a chromosome, recombination hot spots, gene clusters, large genomes, linkage drag, repair mechanisms and epigenetic effects allow some changes and gene combinations to occur more frequently than others, while some have to be considered as unlikely or even very unlikely.
- The situation in regard to SDN-1 and SDN-2 applications is very different in at least three aspects: (1) these applications (in most cases) are not meant to increase genetic diversity in a non-targeted way. Therefore, unintended changes in the genome have to be seen as undesirable effects; (2) CRISPR/Cas makes a much larger part of the genome available for genetic change compared to conventional breeding; it allows biological characteristics to be generated that were not previously achievable; (3) complex characteristics cannot be generated with the new methods of genetic engineering if these are not well defined at the genomic level. Thus, in many cases, QTLs might not be so easily achieved by using SDN-1 and SDN-2.
The authors conclude that, in general, higher precision in changing the genome does not necessarily result in greater safety or higher success rates in plant breeding. Imprecise modifications, such as those resulting from ‘random’ mutagenesis, can be safe as well as beneficial. The authors identified the following aspects as particularly important for regulatory decision-making:
- New patterns of genetic change and resulting genetic combinations are, in many cases, likely to result from the application of SDN-1 and SDN-2.
- The applications of ‘old’ methods of genetic engineering (such as biolistic methods or Agrobacterium tumefaciens) used in most cases to introduce the CRISPR/Cas component into the plant cells can cause a broad range of unintended effects.
- CRISPR/Cas technology itself can cause many specific unintended effects; these would be dependent on the individual process, the surrounding experimental parameters, the chosen target location, on the genome and the specific organism. Therefore, each specific case must be investigated. In many cases, this challenge in risk assessment goes far beyond what is discussed as ‘off-target effects’. The report uses selected examples to provide a greater understanding of regulatory challenges resulting from SDN-1 and SDN-2 applications. The examples are grouped into five categories:
Changes in the composition of plants that may impact the food web
It was shown that changes in plant ingredients such as oil, protein, starch or other biologically active ingredients (such as plant estrogens or vitamins) can have an effect, e.g. on mammalian wildlife species, birds and insects as well as their related food webs. Particularly, if the intended changes in plant composition exceed the range of those in conventionally bred plants, the impact on the food web and the food and feed production chain should be extensively investigated as part of environmental risk assessment. In this context, risk assessment also has to take into account unintended effects that may cause changes in the composition of plants.
Changes in the composition of plants that may impact plant communication and interaction with the environment
The report shows that changes in plant composition can also affect communication and interactions with organisms which do not feed on them but are associated in other ways, e.g. cooperation (such as beneficial insects, e.g. predators or pollinators), or symbionts (such as the plant’s microbiome) or also organisms that attack the plants (so-called ‘pest’ insects). It concludes that the impact on plant communication and interaction with the interconnected environment should undergo detailed environmental risk assessment, especially in cases where the intended changes in plant composition exceed the range of what is known from conventionally bred plants. In this context, risk assessment also has to take unintended effects that may impact plant communication into account.
Changes in the biological characteristics of the GE organisms meant to enhance fitness
A few examples are available of plants where enhanced fitness is intended by the trait, including increased drought tolerance, resistance to pest infestation or to plant diseases caused by viruses or fungi. There are several aspects that are important for risk assessment, e.g. expansion of unsustainable agricultural cultivation in, thus far, near-natural habitats or gene flow to natural populations. The authors highlight the example of rice genetically engineered with CRISPR/Cas that is intended for cultivation on ground with a high salinity. Gene flow could occur to wild rice and become particularly problematic for rice growing due to enhanced fitness of the weedy rice. Consequently, plants generated by SDN-1 or SDN-2 showing enhanced fitness should undergo detailed environmental risk assessment, especially in regard to gene flow and next generation effects. In this context, risk assessment also has to take into account effects that may unintentionally enhance fitness in unexpected ways.
Organisms with the potential to persist and propagate in the environment
One important question with regard to the reliability of the risk assessment for genetically engineered organisms is whether these can spread in the environment. If this cannot be ruled out, the authors show that, in many cases, the uncertainties would be so great that they would outweigh other considerations and render risk assessment inconclusive. This is also because multiplex interrelations with the closer and wider environment pose a real challenge for the risk assessor. While genetic stability over several generations might be demonstrated in domesticated varieties under normal field conditions or green house cultivation, genome x environmental interactions and introgression into heterogeneous genetic backgrounds can still trigger unpredictable next generation effects. Therefore, the authors conclude that organisms derived from SDN-1 or SDN-2 applications able to persist and propagate in the environment should undergo especially detailed environmental risk assessment. In this case, measures to prevent uncontrolled spread must be put in place.
Examples with ethical implications, including animal health and welfare, nature protection and rights of future generations
The authors emphasise that the “radical implications of gene editing (…) for our species and our planet” (Doudna & Sternberg, 2017) not only deserve strict regulatory oversight, but also deserve a broad sociological and ethical debate. The intrusion of GE organisms into native populations would not only raise safety issues, but also fundamentally change our understanding of what is considered ‘natural’. Possible consequences could impact all future generations on this planet, including our own species. In this context, the authors recommend the careful consideration of the new concepts, which include strengthening the protection of biodiversity to legally safeguard it as a protected common good for the future.
Further major ethical issues relate to animal welfare and protection. There are already several publications reporting on SDN-1 and SDN-2 and also SDN-3 applications that need mandatory risk assessment. These include applications that can be used on farm animals in order to produce more meat, milk with changed composition, hornless cows, virus-resistant pigs and animals that are adapted to climate change. As discussed in the report, interests in marketing these animals can lead to serious conflicts with well-established social and ethical standards as well as the consensual values of European society.
The authors come to the conclusion that there are several important reasons why organisms derived from applications of SDN-1 and SDN-2 should all have to undergo mandatory risk assessment. In short, the pattern of intended and unintended changes and the resulting new combinations of genetic information arising from genome editing will, in most cases, be different in comparison to those derived from conventional breeding. These differences co-occur with biological characteristics and risks that need to be fully investigated before any conclusions on the safety of the new organisms can be drawn. Detailed examination of an organism’s genetic and overall biological characteristics, starting with the process that was used to generate the organism, is needed to decide whether the organism is safe.
The requirements for regulation as foreseen by current GMO law in the EU are mandatory whether or not additional DNA sequences were inserted. In addition, a broad range of ethical and social issues also have to be taken into account by the regulatory decision-makers.