1. Genome-edited mammals for agriculture

I would like to thank Ana Laura Mello for moderating this discussion and the Secretariat for facilitating it.
My name is Dr Werner Schenkel, I have been working as a risk assessor for the German Competent Authority for about 20 years and have been involved in Cartagena Protocol related issues since 2017.
Having joined last week's discussion late and not fully following the moderator's instructions, I will now try to correct both failures by starting early and following the questions set out to structure the discussion.
1. How does this topic potentially pose challenges to the existing risk assessment frameworks, guidance and methodologies? Do solutions exist?
A very important condition to be met according to CP9/13 Annex I (b) is, that the issue falls within the scope of the Protocol. I do not think that a consensus will be reached on whether or not this condition is met in all cases covered by the topic.
If it is within the scope, I see no reason why this issue should challenge existing risk assessment frameworks, guidelines and methodologies.
Solutions developed for LMOs will generally be suitable for LMOs developed by genome editing.
As mentioned in several post before the problem formulation approach, which relies on pathways to harm (as presented in the additional voluntary guidance materials to support case-by-case risk assessments of living modified organisms (LMOs) containing engineered gene drives), provides a flexible and robust framework for framing and informing case-by-case risk assessments of LMOs.

2. What could be the specific challenges to related to this issue?
The challenges mentioned in the context of this issue relate largely to the questions of potential unintended outcomes as a result of genome editing. Potential unintended outcomes must and will be considered in any risk assessment. Therefore, they are not a challenge specific to this issue.

3. What are the specific issues concerning this topic?

4. Are there existing resources on similar issues that can address this issue or resources that could be adapted to address this need?
Several guidance materials on the risk assessment of LM animals including mammals for agriculture are available. Among others the EFSA “Guidance on the environmental risk assessment of genetically modified animals” (EFSA 2013).

On the basis of the above, I consider that this topic does not meet the criteria set out in decision CP-9/13 for the process of identifying and prioritising specific issues for risk assessment of living modified organisms.

Werner Schenkel

EFSA 2013: https://bch.cbd.int/en/database/BCH-LAW-EU-115260-1

Dear colleagues,
My name is Anastasia Matthies and I work at Federal Office of Consumer Protection, where I am responsible for the risk assessment of LMOs. Firstly, I would like to express my gratitude to the moderators and all participants for the interesting and informative discussion.
I would like to strongly support the contribution of Dr Werner Schenkel [#12404], who argues that this topic does not meet the criteria set out in decision CP-9/13 for the process of identifying and prioritising specific issues for risk assessment of living modified organisms, as existing risk assessment methodologies provide the means to address the challenges of risk assessment of genome edited mammals in agriculture.
1. How does this topic potentially pose challenges to the existing risk assessment frameworks, guidance and methodologies? Do solutions exist?
As mentioned above, resources and guidance developed for LMOs will generally be suitable in their core concept for mammals developed by genome editing. The problem formulation approach, which relies on pathways to harm, provides a flexible and robust framework for framing and informing case-by-case risk assessments of all LMOs. The universality of this concept is based on the fact that it can be flexibly applied to any type of species and modification, because the focus is not on the technology or the organism, but on the process of hazard identification, taking into account all factors (trait, modification, organism, released environment, exposure, etc.) and the resulting pathway to harm. 

2. What could be the specific challenges to related to this issue?
As already noted, potential unintended outcomes must and will be considered in any risk assessment, it is the central aspect of the problem formulation concept. The only challenge (and it is not specific to this issue) is to thoroughly inform the resulting test hypotheses. In essence, the challenge is the practical application of the concept. Therefore, training and capacity-building measures for interested parties should be directed in this direction.

3. What are the specific issues concerning this topic?

4. Are there existing resources on similar issues that can address this issue or resources that could be adapted to address this need?
In addition to the resources already mentioned, I would also like to highlight the activities of EFSA in relation to new developments in biotechnology applied to animals. EFSA is currently preparing a scientific opinion on how the current EFSA guidance on animal risk assessment can be applied to the new developments and what updates may be needed. This opinion will cover farmed animals - mammals, birds, fish and invertebrates - bred to produce food, feed and other agricultural products.

https://connect.efsa.europa.eu/RM/s/consultations/publicconsultation2/a0lTk000003Wxsr/pc1293

Best regards,
Anastasia Matthies

Dear Colleagues,

Thank you, Mr. Schenkel and Ms Matthies, for the firsts interventions on the topic of genome-edited mammals for agriculture and providing valuable inputs towards the posed questions.

I would like to encourage all participants to contribute to this topic and provide insights into this topic before this topic closes on Monday 5 May.

Also, as a kind reminder, I would appreciate if you would be able to share the DOI or URL links when sharing references and resources.

I look forward to the continued discussions,

Ana Laura Mello

Dear All,

My warm thanks to Ana Laura Mello and Anita Anthonysamy for also moderating this second round of discussions.

My name is Piet van der Meer. I am trained as a microbial ecologist and an environmental lawyer, and since 1986 I have conducted hundreds of risk assessments in regulatory context. Since the adoption of the CPB, I also provide training on risk assessment to government- and public research institutions, with the principles and methodology of Annex III as the starting- and endpoint.

I echo the observation in earlier posts that it is important to keep focusing this on line forum on cases that fall under the CPB.

In response to the first question posed by the moderators: I agree with the conclusion in post #12404 that gene edited mammals for agriculture that fall under the CPB do not pose a challenge to the risk assessment methodology as laid down Annex III of the CPB.

The stepwise methodology of Annex III includes:
a) identification of novel characteristics that may have adverse effects (including the identification of  scientifically plausible pathways to any such adverse effects),
b) evaluation of the likelihood of these pathways/effects being realized in a specific case at hand,
c) evaluation of the potential consequences if these effects are realized,
d) estimation of the overall risk, by combining likelihood and consequence, and
e) evaluation whether identified risks are acceptable or manageable, in the context of the risks posed by the non-modified recipients or parental organisms in the likely potential receiving environment.

This Annex III methodology is based on long experience with risk assessment, is scientifically sound and there is nothing in that stepwise methodology that cannot be applied in a scientifically sound manner to gene edited mammals for agriculture.


Piet van der Meer

Esteemed colleagues,

In contribution to discussion I would like to comment on the suggested questions 1 through 3:

1. I must agree from what Dr. Werner Schenkel #12404 has expressed regarding meeting condition b) in Annex 1 of the CP9/13, which poses a challenge in reaching a consensus between Parties if genome edited organisms fall within the scope of the Cartagena Protocol. This regulatory asymmetry creates different perspectives and methodologies to carry out risk assessment related to this topic.

2. Some specific challenges worth mentioning related to this topic are:

- Off-target effects, which occur when genome-editing tools like CRISPR-Cas9 introduce unintended mutations at genomic sites resembling the target sequence, can create modifications that disrupt essential genes and regulatory pathways, potentially leading to unforeseen end products (Guo et al, 2023)

- Genetic mosaicism can lead to variable outcomes in edited organisms, resulting from the presence of multiple alleles in an individual, which manifests in different cells and tissues. This is undesirable as Toranza et al (2023) best stated “This phenomenon appears when DNA replication precedes CRISPR-mediated genome edition and it is undesirable because it reduces greatly the odds for direct KO generation by randomly generated indels”.

- Ethical concerns related to animal rights, unnatural interventions, and experimenting on animals with the sole purpose of human welfare.

3. Although all four of the suggested specific issues may be relevant to this topic, the primary concern should focus on issue ii). Given our current limited and evolving understanding of genome-edited animals, it would be extremely challenging to fully assess the potential risks associated with their release into the environment. Moreover, effectively controlling and mitigating these risks, as well as monitoring, would present significant challenges and potential considerable consequences.

References

- Lamas-Toranzo, I., Galiano-Cogolludo, B., Cornudella-Ardiaca, F., Cobos-Figueroa, J., Ousinde, O., & Bermejo-Álvarez, P. (2019). Strategies to reduce genetic mosaicism following CRISPR-mediated genome edition in bovine embryos. Scientific Reports, 9, 14900. https://doi.org/10.1038/s41598-019-51366-8.

- Zhou, Y., Zhang, Y., Wang, L., Wang, Y., & Zhang, Y. (2023). A novel bioactive glass scaffold combined with platelet-rich plasma for bone regeneration. Frontiers in Bioengineering and Biotechnology, 11, 1143157. https://doi.org/10.3389/fbioe.2023.1143157.

My name is Christoph Then. For my affiliations please see the first round of questions.
In the following, I try to answer to the questions raised by the moderator.

Question 1
In our recent report (Testbiotech 2025), we show that there are specific challenges for risk assessment. We identify risks associated with the processes of genome editing in livestock that can result both from the processes (unintended effects) or their intended outcomes (desired traits). This can affect various aspects of including animal protection, animal welfare, animal health, animal breeding, the environment and also risks for consumers. These issues should be spelled out in a specific guidance for risk assessment.

Question 2
Specific issues may emerge from the close interactions between farmers and animals that can cause pathogenes to increase their range of hosts (like it is observed in the case of the H5 bird flu that is causing outbreaks in U.S. dairy cows with several recent human cases in U.S. dairy and poultry workers). The emergence and distribution of pathogenes is also relevant for transboundary movements and risks to wild and protected species.

Another specific issue is the introduction of unintended genetic changes into larger breeding populations like it was at risk in the case of the hornless cows (Norris et al 2020).

Furthermore, animal welfare and animal health issues caused by the changes in the target genes and the intended and pleiotropic effects that go along are a problem in LM animals. In our report this exemplified in the case of the myostatin gene: Attempts to knock out or influence the function of myostatin gene to enhance growth in muscles have been made in cattle, buffalo, sheep, goats, pigs, rabbits, horses, dogs and fish. This raises a broad range of specific issues related to health, welfare and safety in regard to the LM animals. These issues are caused by intended as well as unintended effects (as shown in our report).

Some of the mammals used in animal production systems such as for example goats, rabbits, or animals for the production of fur have some  potential to escape into the environment.


Question 3
All these questions can be answered with yes.


Question 4
In the EU, new guidance for LMOs derived from new genomic techniques may be developed by EFSA, however the process suffers from inadequate terms of reference (https://www.testbiotech.org/en/news/efsa-intends-to-revise-its-risk-assessment-guidelines-for-ngt-animals/). Not only ‘new risks’ (whatever this should be) are the most relevant issue, but those risks that are specific for this group of LMOs. We hope that our report is helpful in this regard.

Furthermore, it is to be expected that the overall risk potential will increase over the time, since the uncertainties in assessing the risks to human and aninmal health and the environment may increase in parallel with the number of NGT animals authorised, potentially in combination with LM microorganisms and other LMOs. A guidance that addresses cumulative and combinatorial effects will be necessary to take into account systemic risks that go beyond the assessment of single LM animals.

In addition to classical risk assessment, further regulation recommended: The  legislator should set the bar for applications and commercialisation of LM mammals very high. If the bar for market authorisation is set too low, there is a risk of an increase in the number of experiments on animals, animal losses, suffering, pain and impairment of animal welfare due to economic expectations.

References:

Norris A.L., Lee S.S., Greenlees K.J., Tadesse D.A., Miller M.F., Lombardi H.A. (2020) Template plasmid integration in germline genome-edited cattle. Nat Biotechnol, 38(2): 163-164. https://doi.org/10.1038/s41587-019-0394-6

Testbiotech (2025) Use of new genetic engineering in farmed vertebrates: a critical assessment.
https://www.testbiotech.org/publikation/use-of-new-genetic-engineering-in-farmed-vertebrates-a-critical-assessment/

Dear esteemed participants.

Here are a few thoughts that I would like to contribute to this fruitful discussion:

1. How does this topic potentially pose challenges to the existing risk assessment frameworks, guidance, and methodologies? Do solutions exist?
Challenges:

Unclear regulatory status of genome-edited organisms (GEOs): Many genome-edited mammals may not contain foreign DNA and could be indistinguishable from naturally occurring mutations, leading to ambiguity over whether they fall under the definition of an LMO (Living Modified Organism) as per the Cartagena Protocol.

Inadequacy of current RA guidance: Existing frameworks primarily target transgenic organisms and may not account for the diverse types of edits (e.g., base editing, gene knock-outs) or their subtle phenotypic effects.

Off-target and pleiotropic effects: Risk assessment methodologies may not fully capture unintended edits or long-term effects on physiology, reproduction, or ecosystem interactions.

Novel traits with complex phenotypes: Traits like disease resistance or enhanced growth may have ecosystem-wide implications that require adapted ecological modeling and assessment.

Possible solutions:

Updating definitions and scope: Clarifying the treatment of genome-edited organisms within the scope of the Protocol and national biosafety frameworks.

Case-by-case risk assessment: Developing tailored risk assessment methodologies that consider the type of edit, the function of the modified gene, and the receiving environment.

Enhanced molecular characterization techniques: Integration of whole-genome sequencing and bioinformatics tools for detecting off-target edits and characterizing unintended effects.

Guidance supplements: Expanding or adapting existing CBD guidance on risk assessment, especially the Roadmap for Risk Assessment and relevant AHTEG outputs.

2. What could be the specific challenges related to this issue?
Detection and traceability: Unlike traditional GMOs, genome-edited animals may lack identifiable markers, complicating traceability, detection, and regulatory enforcement.

Ethical and animal welfare concerns: Public concerns over editing sentient organisms for productivity traits may influence acceptance and governance.

Gene-environment interactions: Traits such as heat tolerance or disease resistance might behave unpredictably in different ecological contexts.

Cumulative and long-term impacts: Repeated use or release of genome-edited breeds could alter genetic diversity of livestock populations or interact with wild relatives.

Regulatory divergence: Countries vary significantly in their treatment of genome-edited organisms, complicating transboundary movement and international trade.

3. What are the specific issues concerning this topic?
(i) Potential to cause adverse effects on biodiversity and human health, including impacts on IPLCs:
Yes. For example:

Reduction in genetic diversity: Reliance on a few highly productive edited breeds could narrow the genetic base of livestock.

Ecosystem disruption: Escaped animals could outcompete or hybridize with wild relatives, affecting population dynamics.

Risks to indigenous practices: Genome-edited traits could marginalize traditional breeds important to indigenous peoples and local communities (IPLCs).

Food and health implications: Changes in allergenicity or nutritional composition might pose health risks.

(ii) Potential for environmental introduction (deliberate or accidental):
Yes.

Deliberate release: Many genome-edited mammals are intended for agricultural use and may be raised in open systems (e.g., grazing).

Accidental escape: Farmed mammals could escape confinement and establish feral populations, particularly in regions where close relatives exist.

(iii) Potential to disseminate across national borders:
Yes.

Movement of live animals or germplasm (e.g., semen, embryos) can result in cross-border dissemination.

Feral or migratory species (e.g., genome-edited pigs) may naturally cross borders.

(iv) Commercialization status:
In progress or likely.

Research-stage animals with traits such as hornlessness in cattle, disease resistance in pigs, or enhanced productivity are in advanced development.

Some genome-edited animals have received regulatory approval (e.g., hornless cattle in the USA under investigational exemption).

Commercial use may vary widely by jurisdiction, with some treating genome-edited animals as non-GMOs.

4. Are there existing resources on similar issues that can address this issue or resources that could be adapted to address this need?

CBD Roadmap for Risk Assessment of Living Modified Organisms (LMOs)
It provides a structured approach for assessing risks associated with LMOs under the Cartagena Protocol on Biosafety.
https://bch.cbd.int/onlineconferences/guidance_ra_roadmap.shtml

Ossama AbdelKawy
Egypt National Focal Point for the Cartagena Protocol
Microbiology and Biotechnology Professor, British University in Egypt
Research Professor, Egyptian Atomic Energy Authority
Science Advisor, Egyptian Ministry of Environment

Dear colleagues,

I want to thank Ana Laura Mello and Anita Anthonysamy for moderating the discussion and the Secretariat for facilitating it.

My name is Christophe Boëte, I am a research scientist at the IRD (Research Institue for Developement) in France, based at the Institute of Evolutionary Science of Montpellier, France. Most of my research deals with the interactions between mosquito and their pathogens, the evaluation of novel approaches against vectors at the ecological and epidemiological levels as well as the aspects related to their acceptability and the related regulation.I was a member of the AHTEG that worked on the additional voluntary guidance materials to support case-by-case risk assessments of living modified organisms containing engineered gene drives.

1)
Traditonal frameworks often distinguish between LMOs and non-LMOs but GE techniques (such as CRISPR), because they could result in changes that are difficult to detect, can make categorization unclear. This leads to difficulties for the monitoring, the detection and traceability of the GE-animals and this is challenging for transboundary movement and the Advance Informed Agreement (AIA).

The problem formulation approach, relying in the pathway to harm has been mentioned in previous posts (#12404 and #12412) and it is presented as a flexible and robust framework for all LMOs. It has however a number of limitations that are noteworthy to be considered. Among them one might cite an oversimplification of complex interactions including the ecosystem interactions (reduced to a linear cause-effet chain), an individual approach of risks rather than how mutiple hazards interact and a focus on known hazards.

2)
As stated in previous posts (#12423) a number of specific challenges are worth mentioning :
The off-target effects that can lead to unexpected effets. There is no evidence that off-target alterations cannot introduce novel hazards, nor are they predictable. Regarding the edited gene edited hornless cattle, the company that produced such cattle reported no off-target effects. However in 2019, complex genomic rearrangements have been detected in calves (Norris et al., 2019) and bacterial DNA including a gene conferring antibiotic resistance was found in a GE animal (https://www.technologyreview.com/2019/08/29/65364/recombinetics-gene-edited-hornless-cattle-major-dna-screwup/).

As mentioned in post #12428, the question of animal welfare can go along with an unintended effect. The case of lectin modification in GE fish to obtain larger animal leads to the  disruption of satiety and of the control of appetite favouring food intake. The impact of animal welfare remains an undocumented impact.

Greetings again colleagues

This post is relevant to a number of topics including this one and particularly Week 1 topic 5, essentially all topics in Week 2, and topics 1 and 2 of Week 3. I make these comments here because of the content covered by others on this topic.

As this intervention is broad in nature, I will depart from the list of questions to organise my thoughts. In short, I’m supporting the call for guidance and will describe a particular contribution of the guidance I believe would be of value regardless of whether it is for genome edited mammals or any other kind of LMO, but is not explicitly in the list of topics for guidance. This guidance could help to operationalise inter alia Annex III (9)(d) “Insert or inserts and/or characteristics of modification. Genetic characteristics of the inserted nucleic acid and the function it specifies, and/or characteristics of the modification introduced”, both intended and unintended.

I am enjoying and learning from all the responses in this thread, but will make specific reference to #12423, #12428, and #12437 because each author has raised the issue of the unintended insertion of a plasmid into the bovine genome in the construction of the hornless cattle by Recombinetics. In addition to the references provided by others, we also used that event to illustrate shortcomings in existing risk assessment approaches [1].

This famous case illustrates well what I see as the value of new guidance on this issue, and relevant to all the other topics I listed above. “We have all the scientific data that proves that there are no off target effects” said the Recombinetics CEO… [2]. But as others note, the US FDA found inserted the “bacterial plasmid containing various sequences designed for use in molecular biology, including antibiotic resistance [genes]” [3].

How did Recombinetics miss such a large (4 kb) continuous insertion? By their own admission, it just didn’t look for it. “The company did not directly screen for the presence of the plasmid, it should have.” https://recombinetics.com/company-statement-faqs plasmid-remnant-found-first-gene-edited-bull/

There will always be options for how to look for what you did not intend to make. The FDA researchers noted that “Each screening approach carries assumptions and biases that may allow alterations of unexpected types to go undetected” [4]. Guidance can include broadly useful advice on how to recognise the limitations and biases inherent in screening methods, how to use a mix of methods to minimise uncertainties, and provide confidence to the industry as well that they are anticipating the risk assessment needs of Parties and other national regulators. This would be consistent with advice already in the guidance on, for example, choice of comparators.

Norris et al (2020) explained why they but not Recombinetics found the insertion. “Probable reasons include noninclusion of the plasmid backbone in the sequence alignment, elevated noise at the target locus, limited signal of the sequencing data and PCR conditions insensitive to detection of integrations.” Even narrowing the list of unintended outcomes to insertions, there is at present no reliable way to ensure that they do not occur, even when no DNA is purposely added to the genome editing reaction.

On top of the contamination of routine reagents with nucleic acids [5], commercial grade gene editing materials such as the guides (CRISPR) synthesised to work with the site-directed nucleases (e.g. Cas9) are contaminated with other guide fragments [6]. These contaminants might direct the genome editing nuclease to unintended targets in the target genome, or to targets in genomes of unintentionally exposed organisms. They are also potential transgenic material for insertion into the target genome.

In the above example, the commercial grade materials were contaminated with fragments of DNA that had sequences found in animals, fungi, plants, and bacteria. The researchers found DNA fragments that matched SARS-CoV-2 (Covid-19) and human immunodeficiency virus (HIV). They attributed some of the contamination to the DNA synthesising machines [6].

Norris et al also rightly note that “As genome-editing technology evolves, so does our understanding of the unintended alterations it produces, both in form and frequency.” A living guidance, as the guidance has always been intended to be, can help “to derive maximum benefit from the potential that biotechnology has to offer, while minimizing the possible risks to the environment and to human health” (Protocol introduction) by providing regulators with insight into these options and why they were, or should have been, chosen on a case-by-case basis.


1. Heinemann, J.A. et al. (2021) Differentiated Impacts of Human Interventions on Nature: Scaling the Conversation on Regulation of Gene Technologies. Elem Sci Anth 9 (1), 00086.
2. Regalado, A. (2020) Gene-Edited Cattle Have a Major Screwup in Their DNA. https://www.technologyreview.com/2019/08/29/65364/recombinetics-gene-edited-hornless-cattle-major-dna-screwup/, (accessed 30 September 2020).
3. Solomon, S.M. (2020) Genome Editing in Animals: Why Fda Regulation Matters. Nat Biotech 38, 142-143.
4. Norris, A.L. et al. (2020) Template Plasmid Integration in Germline Genome-Edited Cattle. Nat Biotechnol 38 (2), 163-164.
5. Ono, R. et al. (2019) Exosome-Mediated Horizontal Gene Transfer Occurs in Double-Strand Break Repair During Genome Editing. Commun Biol 2, 57.
6. Arakawa, H. et al. (2024) Cross-Contamination of Crispr Guides and Other Unrelated Nucleotide Sequences among Commercial Oligonucleotides. Nucl Acids Res 52 (6), 3137-3145.

Dear colleagues,

I would like to thank the Secretariat and the Moderator for this discussion. My name is Kumitaa and I've been doing genome editing research for close to twenty years. I am also a part of the Genetic Modification Advisory Committee of Malaysia.

I agree with posts #12404, #12423, and #12437, and wanted to add on to question 2. Some of the challenges are tied to the type of editing done. SDN-1 editing does not insert any foreign DNA, and results in a small mutation similar to what could occur naturally or via traditional breeding, and may or may not fall within the scope. SDN-2 and SDN-3 editing is clearer. However, these days, multiplexing is becoming more common. The assessment might be complex when multiple edits of SDN-1 is made, which may lead to a synergistic effect and unexpected outcomes.

The type of construct used is another challenge, and is related to off-target that several colleagues brought up. Depending on the type of construct used, there may be different levels of potential hazard, For example, genome editing with a base editor or a dead Cas9 would result in gene expression changes, but not permanent mutations, versus conventional Cas9 construct, where the off-targets could be permanent mutations or rearrangements. Depending on the depth of analysis and timeframe of the monitoring, it could be taken into consideration to ensure adequate assessment.

For question 4, some resources are:
i) EFSA (EU) Guidance on GM Mammals: https://efsa.onlinelibrary.wiley.com/doi/abs/10.2903/j.efsa.2013.3200
ii) USDA/FDA (USA) Guidance for Genome-Edited Animals: https://www.fda.gov/animal-veterinary/biotechnology-products-cvm-animals-and-animal-food/intentional-genomic-alterations-igas-animals

Dear participants,

My name is Luciana Ambrozevicius, I´m a regulator and a risk assessor at the Brazilian Biosafety Commission. Thank you for the opportunity to participate in the on line forum. For the proposed topic “Genome-edited mammals for agriculture” I would like to make the following considerations regarding the criteria for new topics established in the annex I to decision CP-9/13:

1. How does this topic potentially pose challenges to the existing risk assessment frameworks, guidance and methodologies? Do solutions exist?

At many jurisdiction the GEd mammals do not fall within the scope of the Protocol and a consensus about it will not be reached in a guidance. If a GEd animal is considered to be a LMO, the solutions and procedures already applied for GM mammals will be suitable and the approach and rational of existing guidances, such as the recent guidance about LMO containing gene drive (doc CBD/CP/MOP/11/9), provides a flexible framework to inform case-by-case RA of LM Animals.

I concur with others - no specific challenges for the current RA framework exists and this topic does not fulfill the criteria established for the process for the identification and prioritization of specific issues regarding risk assessment of living modified organisms, according with decision CP-9/13.

Best regards,
Luciana P. Ambrozevicius

Thank you to the moderators for this interesting and timely topic.

I would also like to thank the participants for sharing such important information and expertise on this issue. I support many of the comments made in previous posts, in particular those illustrating the wide profile of unintended effects associated with genome editing. I thus echo and support previous posts including
#12428, #12434 , #12437, #12440.

In our view, the issue of genome edited mammals falls squarely within the criteria of CP 9/13 due to the potential for such LMO applications to cause adverse effects to biodiversity, taking into account human health, and the challenges these applications raise for current RA methods and experiences. LMOs produced through genome editing techniques fall within the definition of an LMO, and thus are not excluded from the Cartagena Protocol. Please see our analysis (available in five languages) (Sirinathsinghji, 2020).

1. How does this topic potentially pose challenges to the existing risk assessment frameworks, guidance and methodologies? Do solutions exist?

The advances in genome editing and their accompanying techniques are expanding the potential range of species being modified, challenging current RA experiences that are lacking in guidance for mammalian species, as well as for genome editing technologies. Such advances now make it possible to produce LMOs in new settings that range from the traditional use of specialists laboratories by trained personnel to making them without specialist facilities even by those with little or no training, and at industrially useful scales. At the same time, numerous proposals and applications for genome edited mammals are advancing, including to commercial stages.

The potential unintended effects resulting from genome editing processes are well established for mammalian species, and well recognised in the biomedical field, where safety aspects are prioritised (e.g. National Academy of Medicine (U.S.) et al., 2020, Hunt et al., 2023). Genetic engineering of mammalian species also involves the use of reproductive techniques e.g. cloning, that are known to cause adverse impacts to the engineered species (Refs below).

Currently, risk assessment guidance materials do not address some of the specific risks associated with genome editing, e.g. unintended effects of the genome editing process and supportive techniques, nor fully address heightened risks and uncertainties of potential unintended effects of traits being introduced e.g. pathogen resistance that are independent of any level of precision, or lack thereof, of genome editing techniques.

2. What could be the specific challenges related to this issue?

- unintended effects of GM process (e.g. on and off-target effects) resulting in potential hazards (e.g. unintended insertion of antibiotic resistance genes in the hornless cattle (Norris et al., 2020), production of novel allergens/toxins with implications for food safety, food webs and wider ecological interactions).
In order to detect such risks, and to maintain alignment with Annex III (e.g. to detect any genotypic or phenotypic changes), updated assessments are warranted to detect such effects. Guidance on techniques such as unbiased ‘omics’ profiling, detailed long-read sequencing would assist in ensuring against such unintended effects.

- Unintended insertions are often dismissed but appear to be a common side effect of genome editing techniques that challenge claims of precision and equivalency to conventionally bred organisms (GeneWatch UK, 2023). This applies to intended SDN-1 outcomes. Relying on intended designs to merely ‘edit’ and not insert genetic material, cannot be relied upon for regulatory purposes for assuming a lack of transgenic insertions. Such effects have been documented and thus relevant to plants, fungi, mammals (including humans) and fish. Such mechanisms provide a pathway for horizontal gene transfer, requiring careful scrutiny. The first documentation of unintended insertions was in mice, and included insertion of vector backbone sequences, as well as cell culture-derived cow and goat DNA, as well as RNA-derived DNA originating from the guide RNA of the CRISPR/Cas9 machinery (Ono et al., 2019). As described in the briefing linked below, the reliance on the cell to repair DNA is a limitation of genome editing. With our understanding of the full range of DNA repair pathways and all their outcomes remaining incomplete, and moreover, the process being outside the full control of the developer, this is an inherent limitation of the technology that undermines claims of precision, predictability or controllability.


- unintended effects and animal welfare issues associated with reproductive supportive techniques such as cloning, that may result in mosaicism, deformities, still births, miscarriages and early animal death. (Kirkden et al., 2012; Megraver et al., 2019; Salvesen et al., 2024, Srirattana et al., 2022). Repeated cloning may also be required (e.g. Mueller et al., 2019).

3. What are the specific issues concerning this topic?

- (i) unintended effects of GM process (e.g. on- and off-target effects) resulting in potential hazards (e.g. transfer of antibiotic resistance genes in the hornless cattle (Norris et al., 2020), production of novel peptides (e.g. Smits et al. 2019, Taludhar et al. 2019) that may include allergens/toxins with implications for food safety, food webs and wider ecological interactions. On- and off- target effects comprise both small insertions and deletions, but also larger structural changes (deletions, duplications, insertions, inversions, translocations, unintended integrations of foreign DNA, and more complex events such as chromothripsis  that are associated with health risks such as tumorigenesis (e.g. see Genewatch 2020); Mou et al., 2017; Kosicki et al., 2018; Leibeowitz et al., 2021). Unintended effects such as bystander mutations, on-target and off-target effects, are easily missed with conventional genotyping methods, warranting new guidance to facilitate detection of unintended effects that may cause adverse impacts to biodiversity and human health

- Unintended effects that are particularly relevant to mammals also include the detection of immune dysregulation (e.g.Simeonov et al., 2019), activation of p53 DNA damage response (Enache et al., 2020).

- Unintended effects of introduced traits raise a high degree of uncertainty that challenges current methods for assessing risk e.g. the potential for evolutionary responses to pathogen-resistant traits. Significant knowledge gaps make protocols for reducing uncertainty a challenge, and not easily resolvable by methods such as computer modelling.

- generating pathogen reservoirs with biosecurity risks of pathogen evolution; novel spillover events. For example, Ikoko-Akoh et al., (2023) on the development of genome edited chickens designed to be resistant to avian flu, reports that the mutations in the bird flu virus unexpectedly allowed the virus, that is usually limited to birds, to use the two shorter proteins, which also occur in humans, and thus the virus partially adapted itself for replication in mammals (potentially including humans). Such risks of unintended viral evolution are also relevant to any other pathogen resistant mammals (or indeed plants), and to the current mammalian applications that in the process of commercialisation.

- A related concern is that a gene edited disease-resistant animal may be infected but not show symptoms of disease, perhaps benefitting the individual animal but putting other animals at increased risk. In animals, these problems are compounded by the difficulties described above in scaling up production to create large herds or flocks: this process is likely to be too slow to keep up with fast evolving pathogens. (see Genewatch, 2025).

- unintended effects introduced by additional reproductive techniques result in specific animal welfare issues. 

- Socio-economic effects could adversely impact traditional and local farming systems, e.g. via unintended impacts such pathogen evolution, displacement of native farming species, divergence of economic resources away from proven or safer solutions (e.g. access to healthcare in the case of health applications). The move towards editing of wild mammalian species may also result in uneven impacts on communities whose livelihoods and cultural integrity is heavily embedded and intertwined with biodiversity, including Indigenous Peoples and local communities.

- Mammals may disseminate across borders by live transport or long-range migration. The proposals to edit wild organisms, as raised by Christoph Then in other posts, further increases the chances unintended transboundary movements.


(iv) Is the LMO already, or are likely to be, commercialized or in use somewhere in the world?

Several genome-edited LMO mammals have been approved or undergone regulatory review, including pigs resistant to Porcine Reproductive and Respiratory Syndrome, ‘heat-tolerant’ cows, and cows with ‘increased yield’, respectively. As raised in the previous discussions on LMO animals, companies working under the bracket of ‘de-extinction’ have also recently publicised the development of genome edited grey wolves, and are working on other mammalian species including red wolves and elephants.

4. Are there existing resources on similar issues that can address this issue or resources that could be adapted to address this need?

There are currently no existing resources that take into consideration the specific challenges and risks related to the genome editing technologies and species considered in this topic.

With regard to the suggestion that the recent guidance materials for LMOs containing engineered gene drives could be used more widely for other LMOs, I would like to highlight that those materials are voluntary. In contrast, Article 15 obligations under the Protocol require risk assessments  to be “carried out in a scientific manner, in accordance with Annex III”, without specifying a type of methodology. In our view, the topic of genome edited mammals meets the criteria under CP9/13, and key to this is that the risk assessments must be in accordance with Annex III.

Reliance on the ‘pathways to harm’ approach as described in the gene drive guidance may fail to provide sufficient considerations of the specific risks and challenges raised by edited mammalian applications (as well as the other topics in this online forum).  Proposals to adopt this approach for all future LMOs focus only on unintended effects of the intended trait, risking missing out the abovementioned central risks of genome editing, which include the unintended effects of the process itself. Moreover, within the voluntary guidance itself, linkages back to specific risks of new technologies (in this case, gene drives) are generally restricted to the mosquito section of the guidance.

Such a narrow implementation of a problem formulation/pathways to harm approach, risks weakening assessments such that that unintended effects and the engineered organism as a whole are not systematically assessed unless they relate to the intended design. For example, if assessment of unintended effects is restricted to the introduced trait, and not the process, any assessment along these lines would not detect on- and off-target effects that include accidental insertion of genetic material, as well as small- and large-scale unintended changes to the genome as has occurred in the case of the hornless cattle. If claims of equivalency with conventionally-bred animals are assumed for edited animals with no intended insertions, then no pathways to harm would be selected to assess unintended genotypic and phenotypic changes such as this. The selective approach to testing also challenges alignment with the precautionary approach,

Another challenge to the precautionary approach is that this method focuses on the proof of harm in a causal chain of events, rather than risk.

The gene drive guidance also relies heavily on modelling to reduce uncertainties; however such methods are insufficient where significant knowledge gaps remain on e.g. evolutionary dynamics of pathogens in response to disease-resistant mammals.

As such, we do not think that the gene drive guidance/pathways to harm approach is suitable to be repurposed for any new and evolving challenges to risk assessment (including for LMO microorganisms, animals, plants, edited mammals as well as the use of CRISPR expressing machinery for pest/pathogen control that are being discussed on other threads).

GeneWatch UK (2025) Gene Editing: Is anyone really being left behind? https://www.genewatch.org/uploads/f03c6d66a9b354535738483c1c3d49e4/gene-editing-left-behind-fin.pdf

GeneWatch UK (2023) On-target effects of genome editing techniques: (Un)repaired DNA damage, a hinderance to safety and development?
https://www.genewatch.org/uploads/f03c6d66a9b354535738483c1c3d49e4/updated-genome-editing-techniques-un-repaired-mutations-hindering-safety-and-development-fin.pdf.

Sirinathsinghji (2020) Why Genome Edited Organisms are not Excluded from the Cartagena Protocol on Biosafety. Third World Network/GeneWatch UK.  https://biosafety-info.net/new-publications/why-genome-edited-organisms-are-not-excluded-from-the-cartagena-protocol/

Enache, O. M., Rendo, V., Abdusamad, M., Lam, D., Davison, D., Pal, S., Currimjee, N., Hess, J., Pantel, S., Nag, A., Thorner, A. R., Doench, J. G., Vazquez, F., Beroukhim, R., Golub, T. R., & Ben-David, U. (2020). Cas9 activates the p53 pathway and selects for p53-inactivating mutations. Nature Genetics, 52(7), 662–668. https://doi.org/10.1038/s41588-020-0623-4

Hunt JMT, Samson CA, Rand AD, Sheppard HM. Unintended CRISPR-Cas9 editing outcomes: a review of the detection and prevalence of structural variants generated by gene-editing in human cells. Hum Genet. 2023 Jun;142(6):705-720. doi: 10.1007/s00439-023-02561-1. Epub 2023 Apr 24. PMID: 37093294; PMCID: PMC10182114.

Kosicki, M., Tomberg, K. & Bradley, A. Repair of double-strand breaks induced by CRISPR–Cas9 leads to large deletions and complex rearrangements. Nat Biotechnol 36, 765–771 (2018). https://doi.org/10.1038/nbt.4192

National Academy of Medicine (U.S.), National Academy of Sciences (U.S.), & RoyalSociety (Great Britain) (Eds.). (2020). Heritable human genome editing. the National Academies Press.
Simeonov, D. R., Brandt, A. J., Chan, A. Y., Cortez, J. T., Li, Z., Woo, J. M., Lee, Y., Carvalho, C. M. B., Indart, A. C., Roth, T. L., Zou, J., May, A. P., Lupski, J. R., Anderson, M. S., Buaas, F. W., Rokhsar, D. S., & Marson, A. (2019). A large CRISPR-induced bystander mutation causes immune dysregulation. Communications Biology, 2(1), 70. https://doi.org/10.1038/s42003-019-0321-x

Tuladhar R et al (2019). Nat Commun 10, 4056 (2019). https://www.nature.com/articles/s41467-019-12028-5

Smits AH et al (2019). Nat Methods 16, 1087–1093. https://www.nature.com/articles/s41592-019-0614-5

Idoko-Akoh, A., Goldhill, D. H., Sheppard, C. M., Bialy, D., Quantrill, J. L., Sukhova, K., Brown, J. C., Richardson, S., Campbell, C., Taylor, L., Sherman, A., Nazki, S., Long, J. S., Skinner, M. A., Shelton, H., Sang, H. M., Barclay, W. S., & McGrew, M. J. (2023). Creating resistance to avian influenza infection through genome editing of the ANP32 gene family. Nature Communications, 14, 6136. https://doi.org/10.1038/s41467-023-41476-3

Kirkden, R. D., & Broom, D. M. (2012). Welfare of Genetically Modified and Cloned Animals Used for Food. Retrieved from Compassion in World Farming (CIWF) website: https://www.ciwf.org.uk/media/4237869/welfare_of_genetically_modified_and_cloned_an imals_used_in_food.pdf

Leibowitz ML, Papathanasiou S, Doerfler PA, Blaine LJ, Sun L, Yao Y, Zhang CZ, Weiss MJ, Pellman D. Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing. Nat Genet. 2021 Jun;53(6):895-905. doi: 10.1038/s41588-021-00838-7. Epub 2021 Apr 12. PMID: 33846636; PMCID: PMC8192433.

Mehravar, M., Shirazi, A., Nazari, M., & Banan, M. (2019). Mosaicism in CRISPR/Cas9- mediated genome editing. Developmental Biology, 445(2), 156–162. https://doi.org/10.1016/j.ydbio.2018.10.008

Mueller, M. L., Cole, J. B., Sonstegard, T. S., & Van Eenennaam, A. L. (2019). Comparison of gene editing versus conventional breeding to introgress the POLLED allele into the US dairy cattle population. Journal of Dairy Science, 102(5), 4215–4226. https://doi.org/10.3168/jds.2018-15892

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Academies Press.

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Ono, R., Yasuhiko, Y., Aisaki, K., Kitajima, S., Kanno, J., & Hirabayashi, Y. (2019). Exosome-mediated horizontal gene transfer occurs in double-strand break repair during genome editing. Communications Biology, 2(1), 57.

Salvesen, H. A., Grupen, C. G., & McFarlane, G. R. (2024). Tackling mosaicism in gene edited livestock. Frontiers in Animal Science, 5. https://doi.org/10.3389/fanim.2024.1368155

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Tan, W., Proudfoot, C., Lillico, S. G., & Whitelaw, C. B. A. (2016). Gene targeting, genome editing: from Dolly to editors. Transgenic Research, 25(3), 273–287. https://doi.org/10.1007/s11248-016-9932-x

Dear colleagues,

I'd like to thank to the moderators and to the Secretariat for facilitating this forum, which has been very illustrative.

Recently, the number of studies reporting research in mammals produced for agricultural purposes has increased: ruminants (cattle, sheep, goats, n=63); monogastrics (pigs and rabbits, n=60) modified by genome editing (CRISPR-Cas9), engineered for various porpoises: Yield (32%), reproduction (21%) disease resistance (17%) are the most commonly targeted traits (1). Nevertheless, there are other traits that have been researched: Hypoallergenic properties, behavioral characteristics, etc.

Although publications are still mostly proof-of-concept, this genetic engineering technique has been shown not as precise and safety as argued. Insertions-deletions of genetic material (INDELs), chromosomal damage have been reported in several organisms (2-12).

Since it is commonly assumed that animals are more “biologically complex” than plants, potential detrimental effects at regulatory (i.e. micro RNA), genomic, epigenomic, proteomic, metabolomic levels of gene edited organisms (animals) could appear (13-16), posing risks to environment and human health by consuming LM animals (i.e. new unknown allergens). Since the risk assessment guidance are currently aimed to assess GM plants, there are no risk assessment guidance for breeding, industrial production, environmental consequences, and health effects of gene edited animals for industrial uses. For example, the myostatin gene edited pig (18) and recently, the CRISPR-Cas edited pig cleared for human consumption in the USA (24), could be potentially consumed by a large amount of population in many countries without previous history of safe consumption.

Risk assessment guidance should be developed for LM animals in a case-by-case approach, taking in consideration different zootechnic aspects, such as the possible narrow genetic diversity of the varieties commonly used as a breeding stock, and the potential immune behavior of the cattle. This, echoing the comments #12428 #12434 #12440 #12450 from colleagues. 

Moreover, an essential step on the risk assessment of genome edited animals, is the possibility of identifying potential alterations, insertions and deletions in the genomes (16-17), while detection and identification technologies advances, developing countries could be left behind (19-20). In the context of trade agreements between countries, import of gene editing products (i.e. meat), technical capacities should be installed, particularly in developing countries.  Additionally, in many developing countries, animals used for agriculture involve complex socio-economic networks (21-23). For example, cattle are frequently moved between borders informally and without any zootechnical nor sanitarian examination. The eventual presence of GE animals could pose risk to the economies and social relationships of ILPCs. 

Best regards,
Emmanuel González-Ortega

References
1. Global status of gene edited animals for agricultural applications. https://doi.org/10.1016/j.tvjl.2024.106142
2. Genome editing with the HDR-enhancing DNA-PKcs inhibitor AZD7648 causes large-scale genomic alterations https://doi.org/10.1038/s41587-024-02488-6
3. Template plasmid integra- tion in germline genome-edited cattle. Nat Biotechnol, 38(2): 163-164. https://doi.org/10.1038/s41587-019-0394-6 
4. Chromosomal Rearrangements and Chromothripsis: The Alternative End Generation Model https://doi.org/10.3390/ijms24010794
5. Leibowitz M.L., Papathanasiou S., Doerfler P.A., Blaine L.J., Sun L., Yao Y., Zhang C.-Z., Weiss M.J., Pellman D. (2021) Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing. Nat Genet, 53(6): 895-905. https://doi.org/10.1038/s41588-021-00838-7 
6. Generate a new crucian carp (Carassius auratus) strain without intermuscular bones by knocking out bmp6 https://doi.org/10.1016/j.aquaculture.2023.739407
7. Joint single-cell profiling of CRISPR-Cas9 edits and transcriptomes reveals widespread off-target events and their effects on gene expression https://doi.org/10.1101/2025.02.07.636966
8. The complex architecture and epigenomic impact of plant T-DNA insertions. https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007819
9. An Agrobacterium-delivered CRISPR/Cas9 system for high-frequency targeted mutagenesis in maize https://onlinelibrary.wiley.com/doi/10.1111/pbi.12611
10. Highly Efficient and Heritable Targeted Mutagenesis in Wheat via the Agrobacterium tumefaciens-Mediated CRISPR/Cas9 System https://www.mdpi.com/1422-0067/20/17/4257
11. Site-directed mutagenesis by biolistic transformation efficiently generates inheritable mutations in a targeted locus in soybean somatic embryos and transgene-free descendants in the T1 generation https://link.springer.com/article/10.1007/s11248-020-00229-4
12. Efficient DNA-free genome editing of bread wheat using CRISPR/Cas9 ribonucleoprotein complexes https://doi.org/10.1038/ncomms14261  
13. Roles and regulation of histone methylation in animal development https://www.nature.com/articles/s41580-019-0151-1
14. Pioneer Transcription Factors Initiating Gene Network Changes https://doi.org/10.1146/annurev-genet-030220-015007
15. Gene regulatory network inference in the era of single-cell multi-omics https://www.nature.com/articles/s41576-023-00618-5
16. INDEL detection, the ‘Achilles heel’ of precise genome editing: a survey of methods for accurate profiling of gene editing induced indels https://academic.oup.com/nar/article/48/21/11958/5973460
17. Off-target effects in CRISPR/Cas9 gene editing https://doi.org/10.3389/fbioe.2023.1143157
18. Precise editing of myostatin signal peptide by CRISPR/Cas9 increases the muscle mass of Liang Guang Small Spotted pigs. Transgenic Res, 29(1): 149-163. https://doi.org/10.1007/s11248-020-00188-w 
19. Genetically Modified Organisms: Concerns and Biosafety https://www.taylorfrancis.com/chapters/edit/10.1201/9781003378273-12/genetically-modified-organisms-concerns-biosafety-muhammad-ishtiaq-mubashir-mazhar-mehwish-maqbool-muhammad-waqas-mazhar
20. Public Perception of Genetically Modified Organisms and the Implementation of Biosafety Measures in Kenya https://doi.org/10.1155/2024/5544617
21. Socio-Economic Feature Stirring Women Participation In Livestock Activities https://pjsr.com.pk/wp-content/uploads/2021/11/2.-Vol-3.-Issue-4.-Dec-2021-Ikram-Ullah-Nosheen-Naz-Socio-Economic-Feature-Stirring-Women-Participation.pdf
22. Present Scenario and Role of Livestock Sector in Rural Economy of India: A Review http://dx.doi.org/10.5455/ijlr.20200701051344
23. The effect of animal husbandry on economic growth: Evidence from 13 provinces of North China. https://www.frontiersin.org/journals/environmental-science/articles/10.3389/fenvs.2022.1085219/full
24. https://www.technologyreview.com/2025/05/02/1116059/the-us-approves-crispr-pigs-for-food/

Dear colleagues,

Thank you all very much for your contributions. I appreciate the exchange and the provision of references, which will undoubtedly be a very valuable contribution to the work of the AHTEG. For those who haven't yet participated, please remember that you have until 11 a.m. tomorrow (Montreal time).

Best regards,

Ana Laura

Dear participants,

Regarding the point 4)
The work by EFSA has been mentioned in several posts including the recent ‘Draft scientific opinion on new developments in biotechnology applied to animals: an assessment of the adequacy and sufficiency of current EFSA guidance for animal risk assessment’. This draft document was recently submitted to a public consultation and it is noteworthy to mention that this document presents several gaps. Here are a couple of them:  the presentation of the level of predictability of off-target mutations described as high, the absence of mention of the failure in GE in livestock breeding programs (mosaicism with CRISPR see Mehravar et al. 2019; Salvesen et al. 2024), the lack of information about pesticide-resistant bees (Jayaweera et al. 2024 : https://www.horticulture.com.au/globalassets/laserfiche/assets/project-reports/ph22000/ph22000-final-report.pdf) and the limitation of GE with Diptera (Shirai et al. 2022.), the loss of biodiversity not being considered as an environmental risk.

Overall this reports fails to consider a number of uncertainties that have been highlighted in peer-reviewed publications.
Best regards,
Christophe Boëte


Mehravar M, Shirazi A, Nazari M, Banan M. Mosaicism in CRISPR/Cas9-mediated genome editing. Dev Biol. 2019 Jan 15;445(2):156-162. doi: 10.1016/j.ydbio.2018.10.008.
Salvesen HA, Grupen CG and McFarlane GR (2024) Tackling mosaicism in gene edited livestock. Front. Anim. Sci. 5:1368155. doi: 10.3389/fanim.2024.1368155
Shirai Y, Piulachs MD, Belles X, Daimon T. DIPA-CRISPR is a simple and accessible method for insect gene editing. Cell Rep Methods. 2022 May 16;2(5):100215. doi: 10.1016/j.crmeth.2022.100215.

Thankyou Ana for moderating and greetings to all participants

I would like to respond to a previous post that suggests a number of noteworthy limitations to the problem formulation approach, in particular: (i) an oversimplification of complex interactions including the ecosystem interactions (reduced to a linear cause-effect chain), (ii) an individual approach of risks rather than how mutiple hazards interact and (iii) a focus on known hazards.

The risk pathways within a problem formulation exercise are often portrayed as a linear cause-effect chain for communication and presentation purposes, and to facilitate one of the key objectives of problem formulation, that is the identification of laboratory tests, analysis and field observations that can be used to generate evidence to indicate that a risk pathway will not in fact lead to harmful outcomes.

The linear presentation of a risk pathway, however, does not imply that the cause-effect chain is linear, nor does it imply that the hazards addressed by the pathway are independent of other relevant hazards. The steps within a linear presentation of a pathway to harm may entail complex, non-linear interactions, with feed-back and other system-wide interactions, and this can be reflected within the types of testing strategies or analysis methods that are recommended by the exercise.

The linear portrayal of a risk pathway should not be interpreted as a linear simplification of a complex system. To illustrate with an example: Problem formulation can identify the potential for the relative abundance of species at a location to change following an anthropogenic intervention without having to portray the complex competitive interactions between (and within) the populations of the individual species and the many environmental factors at the locality that may influence their individual birth and death rates. This portrayal would typically occur at other parts of the risk assessment, for example during the description of the model used to predict changes in relative abundance.

Problem Formulation also does not require the analyst to focus on hazards that have been known to occur in the past. The extent to which a risk assessment is able to identify all the possible ways in which a new technology may lead to harm is limited only by the imagination and expertise of those involved in the assessment. This is a facet of all risk assessments and is not particular to Problem Formulation.

Dear colleagues,
My name is Ediner Fuentes-Campos, Deputy Director of Research and Development at the Secretariat of Sciences of Panama. I have been working as a risk assessor at the National Biosafety Commission for GMOs and as a public researcher.

I would like to express my gratitude to the moderator for this important forum and to all participants for their valuable contributions. After reviewing the different interventions, I would like to offer some comments on the topic of genome-edited mammals for agriculture.

I fully support the positions expressed in posts #12404, #12412 and #12421, which clearly state that this topic does not meet the criteria established in decision CP-9/13 for the process of identifying and prioritizing specific issues for risk assessment.

A fundamental point that we must not lose sight of is that genetically edited mammals, particularly those that do not contain foreign DNA, are not clearly described as genetically modified organisms within the scope of the Cartagena Protocol. This regulatory ambiguity, as noted in post #12423, creates different perspectives and methodologies among the Parties.

I agree with post #12445 that in many jurisdictions, genetically edited mammals do not fall within the scope of the Protocol and a consensus on this matter will hardly be reached. This condition, referred to in post #12404, is a fundamental requirement that must be met according to CP9/13 Annex I (b).

The step-by-step methodology described in Annex III of the Protocol, as detailed in post #12421, is based on long experience with risk assessment and is scientifically sound. There is nothing in this methodology that cannot be scientifically applied to genetically edited mammals for agriculture, if these were to be considered within the scope of the Protocol.

Respectfully,
Ediner Fuentes-Campos

Hi,

My name is Enrykie Fortajada, a Fellow from the National Committee on Biosafety of the Philippines. Thank you for this opportunity to be able to contribute to the discussion. For the topic genome edited mammals for agriculture, I would like to raise this concern for consideration, particularly on the number 1 question:
1. How does this topic potentially pose challenges to the existing risk assessment frameworks, guidance, and methodologies? Do solutions exist?

Cutting-edge technologies, such as CRISPR/Cas9, play a key role in improving traits such as disease resistance, growth rate, and feed efficiency, demonstrating the technology’s broader application in livestock. A common issue with gene editing in livestock zygotes is the high incidence of genetic mosaicism. Genetic mosaicism, characterized by a single individual carrying distinct genotypes in different cell lineages, can lead to inconsistent presentation of a desired trait phenotypically, or the absence of the intended genotype in the animal’s germline. This is a concern because genetic mosaicism disrupts the foundational assumptions of uniformity in current risk assessment models. I believe this should be addressed in the guidelines, to involve more sensitive diagnostic technologies, and context-aware interpretation frameworks to ensure accurate and equitable risk assessment. Salvesen et al. (2024) discussed alternatives to direct zygote gene editing, including surrogate sire technology and blastomere separation, that could reduce mosaicism in mammalian livestock.

Reference:
Salvesen, H. A., Grupen, C. G., & McFarlane, G. R. (2024). Tackling mosaicism in gene edited livestock. Frontiers in animal science, 5, 1368155.

In my view, the topic of genome-edited mammals for agriculture does not meet the criteria set out in decision CP-9/13 for the process of identifying and prioritising specific issues for risk assessment of LMOs for the following reasons:

• Genome-edited mammals may not contain foreign DNA, leading to uncertainty about whether they fall under the definition of LMOs as per the Cartagena Protocol
• Existing risk assessment frameworks, guidelines and methodologies for LMOs will generally be suitable for those genome-edited mammals falling within the scope of the Protocol
• Existing risk assessment methodologies provide reliable means to address the challenges posed by new biotechnologies. The problem formulation approach, based on pathways to harm, is flexible and robust enough to frame and inform case-by-case risk assessments of LMOs
• Potential unintended outcomes must and will be considered in any risk assessment. These are not challenges specific to genome-edited mammals
• Several guidance materials on the risk assessment of LM animals, including mammals for agriculture, are available (e.g., https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2013.3200). Additionally, EFSA recently released a draft scientific opinion on new developments in biotechnology applied to animals for public consultation. In this opinion, the adequacy and sufficiency of current EFSA guidance for animal risk assessment are assessed (https://connect.efsa.europa.eu/RM/s/consultations/publicconsultation2/a0lTk000003Wxsr/pc1293)

Dear all,

My name is Eder Toppa, and I have been working for the Brazilian Ministry of Agriculture and Livestock for the past decade. I am currently the Head of the Biosafety Service and a member of the National Biosafety Commission.

The Ad Hoc Technical Expert Group (AHTEG) on Risk Assessment of the Cartagena Protocol addressed essentially the same topics as in its 2024 report (document CBD/CP/RA/AHTEG/2024/1/3): genome-edited animals, the Protocol’s scope, and guidance development. Notably, the group concluded just a year ago that there was insufficient information to prioritize guidance development on this topic, as per CP9/13 Annex I, and since then, no significant new information has been identified.

It is important to note that not all genetically altered organisms fall within the scope of the Cartagena Protocol. Even if gene-edited animals were considered within the Protocol’s scope, existing risk assessment frameworks would still apply. These tools, designed for living modified organisms (LMOs), are flexible enough to evaluate cases such as SDN-3, ensuring a science-based, case-by-case approach in which problem formulation systematically identifies risks by tracing pathways to harm.

Given this, I strongly emphasize that resource constraints require us to prioritize more pressing issues to avoid redundancy and duplication of effort.

Eder Victor Braganti Toppa
Federal Inspector
Head of the GMO Biosafety Service
Plant Health Department
Ministry of Agriculture and Livestock

Dear all,

Contributing to the discussion, I would like to share the perspective of what is done in Argentina.

1. How does this topic potentially pose challenges to the existing risk assessment frameworks, guidance and methodologies? Do solutions exist?

In many producer and agro-exporting countries, such as Argentina, products obtained through NBTs, including those produced by gene editing, are addressed under specific regulations that allow for a determination process to establish whether the new product is a GMO or not.
This determination process is conducted on a case-by-case basis, and if the product is determined not to be a GMO, it is regulated in the same manner as a product obtained through conventional breeding techniques.
In this regard, and for the purpose of addressing genome-edited mammals for agriculture, Argentina sees no obstacle in addressing them under the current regulations and guidelines available.

2. What could be the specific challenges to related to this issue?

The challenge is to harmonize regulations and achieve a consistent approach across all countries for products obtained through NBTs.

3. What are the specific issues concerning this topic?

(i) Is there the potential to cause adverse effects on biodiversity, in particular those that are serious or irreversible, taking into account the urgent need to protect specific aspects of biodiversity, such as an endemic/rare species or a unique habitat or ecosystem, taking into account risks to human health and the value of biological diversity to indigenous peoples and local communities?

No potential adverse effects have been identified.

(iii) Is there the potential to disseminate across national borders?

Yes, but if the NBT product has been evaluated by the Argentine regulatory agency and determined not to be a GMO, it will follow the conventional regulatory pathways for any product entering the country.

(iv) Is the LMO already, or are likely to be, commercialized or in use somewhere in the world?

If the product obtained through NBTs is analyzed and considered conventional, it is not an LMO.

Dear colleagues,

My name is Anita Greiter. I am an ecologist working at the Environment Agency Austria on biosafety issues since 2009. I am also BCH National Focal Point for Austria.
I would like to thank Ana Laura Mello for moderating this discussion and the participants of this forum for the discussion and all the information provided.

Regarding question 1: I would like to echo previous postings regarding the issue of the regulatory status and the availability of information (status of develeopment/commercialisation, regulatory status,  methods used in the transformation). I would like to add, that often various methods are used in the modification of an animal, combining e.g. genome editing methods and transgenesis.

Regarding potential effects on biodiversity, also behavioural changes need to be considered. Another issue specific for farmed animals are animal welfare aspects (being a cross-cutting issue in risk assessment and socio-economic considerations.)

Regarding question 3: Depending on the production system of the specific animal (which vary in different countries), there is a high potential for introduction into the environment and crossing of national borders.

Regarding commercialisation status I would like to refer to a recent horizon scan activity:
Miklau, M.; Burn, S.-J.; Eckerstorfer, M.; Dolezel, M.; Greiter, A.; Heissenberger, A.; Hörtenhuber, S.; Zollitsch, W.; Hagen, K. Horizon scanning of potential environmental applications of terrestrial animals, fish, algae and microorganisms produced by genetic modification, including the use of new genomic techniques. Front. Genome Ed. 2024, 6, 1376927 https://www.frontiersin.org/journals/genome-editing/articles/10.3389/fgeed.2024.1376927/full

Thank you
Anita

As always, with gratitude to the CBD Secretariat and to Ms. Mello for moderating the forum,

I would like to offer strong agreement with posts 12404, 12412, 12421, 12480, and 12482 that this topic simply doesn't meet the criteria for consideration of developing new guidance.  I think post 12445 correctly points out that the development of guidance under the CBD is simply not the place to address policy differences between Parties, and that the chance of successfully completing a guidance document on this subject to be approved or endorsed by the Parties is functionally zero.  There are better ways to spend the time, money and effort that would be required.

I'd also like to thank and greatly support Dr. Keith Hayes in post 12463 for correcting some of the rampant misinformation being proposed here regarding risk assessment, in general, and Problem Formulation as a process.  Many of the posts in this  thread (and indeed the other threads as well) seem to greatly misunderstand the fundamentals of the existing risk assessment process to require an endless information collection process towards addressing the endless possibilities that can be imagined for speculative risk. 

Kind Regards,
Andrew Roberts, PhD
Agriculture & Food Systems Institute

Dear colleagues
Thank you to the moderators and Secretariat of the CBD for this opportunity to interact on these and other topics related to genome editing. I'm ROUAMBA Mathurin, BCH focal point and in charge of evaluation and control at the Agence Nationale de Biosécurité, Burkina Faso's national competent authority. I also apologize for not following the moderators' questions.
In response to questions Q1, Q2 and Q3, I would like to say that Organisms produced by genome editing do not call into question existing guidelines and methodologies for risk assessment. Products derived from genome editing, whether or not they are considered GMOs, are always subject to control of their effects on the environment and human health. This control is carried out by the competent authorities when the products are considered LMOs, otherwise by other regulatory structures.
The specific challenges associated with LMOs derived from genome editing or new technologies lie more in capacity building, experience sharing and collaboration between nations. Some countries have proven experience in assessing and managing the risks associated with these types of LMOs. These countries could share experiences and data related to these LMOs and thus enable other countries to learn and build their capacity. I therefore support the proposals made by some speakers on the transportability of LMO-related data. I also agree with Dr. Keith Hayes on Problem Formulation as a process. I also share with you this article by Ledesma et Eenennaam on the general status of genome-edited VM animals.
Thank you

Ledesma AV, Van Eenennaam AL. (2024) Global status of gene edited animals for agricultural applications. Vet J. 2024 Jun; 305:106142. doi: 10.1016/j.tvjl.2024.106142. Epub 2024 May 22. PMID: 38788996.
https://pubmed.ncbi.nlm.nih.gov/38788996/

Dear colleagues,

I appreciate very much the information and thoughts shared in this thread, some of which I had not been aware of until now. Thus thank you all.

I will attempt to respond to the questions in sequence, but the individual responses could fit to different questions.

Also, this is a longer post, as I am responding to some issues in general, which therefor would also be relevant for all other topics.


1. How does this topic potentially pose challenges to the existing risk assessment frameworks, guidance and methodologies? Do solutions exist?

When the Cartagena Protocol was negotiated, for many the main focus at the time was on LM plants, in particular LM crops, as that was what was coming on the market and what was to be traded between countries. Obviously, the protocol itself is defining LMOs across the whole range of taxa, and its provisions are equally applicable across the whole range, requiring parties to prevent or reduce the risks to biological diversity, taking also into account risks to human health.

Whilst agricultural LM crops have been much in focus of development of voluntary guidance material, agricultural LM animals have not. I regard LM mammals for agriculture (such as sheep, goats, cows & cattle, rabbits, horses, donkeys, buffaloes, bison, zebus, gayal, pigs/swine, deer, llamas, dromedary camel, elk, moose, guinea pig etc.) to be within the scope of the protocol, and genome edited agricultural mammals being a category within these.

With genome editing widely advancing, such genetic modification of farm mammals is becoming more prevalent both in research and in actual application, yet there is little if any guidance as to how to identify and address risk or potential adverse effects of LM mammals in agriculture – whether direct or indirect - on the conservation and sustainable use of biological diversity, including risks to human health.

As pointed out by many in this thread, including also in the original party submission to this topic, there are many categories (areas of concern) that could be affected, e.g. animal health (both on farm and off farm), also impacting animals and biodiversity beyond the farm, in the wider environment, including in the wild; animal welfare; pathogen development and spread, including jumping species; ecosystem -including agricultural ecosystem- interactions, ecosystem functions and services; human health; 

The challenges derive both from the methodology & technology used, i.e. genome editing and its linked processes – and their intended and unintended effects, as well as the target being farm mammals in the context of (direct and indirect) adverse impacts on the conservation and sustainable use of biodiversity, also taking into account human health.

Genome editing is a new and moving technology and guidance – in particular here for mammals in agriculture. Genetic engineering is not static, its tools, targets and applications have been expanding, changing, developing.

I find the instructions of Article 13 of the Protocol very helpful in that it requires two elements for a (robust) risk assessment: to a) carry it out in scientifically sound manner and b) to do so in accordance with Annex III. As technology moves on, Annex III is -obviously- not specific for any particular target or technology or application. It is my understanding that the development of voluntary guidance material is meant to help with specific aspects and developments, thus being rather specific than overly general.

I saw some colleagues suggesting to instead of developing specific voluntary guidance material to rather resort to another general approach, namely the “problem formulation approach which relies on the pathways to harm (as presented in the additional voluntary guidance materials to support case-by-case risk assessments of living modified organisms (LMOs) containing engineered gene drives)” (e.g. here Werner Schenkel, #12404, but similar or identical phrasings were provided also by others).

However, this does not provide specific additional voluntary guidance material for the subject in question, and does not cater for the needs expressed and the guidance material needed. Additionally, there is a wider concern with this particular ‘Problem formulation and Pathway to harm approach’.

I share the concern of others about potential shortcomings and limitations of this approach, for example regarding the risk of oversimplification of complex interactive systems and the possible reduction of complex interactive risks and hazards to linear individual cause and effect chains, thus failing to fully assess the whole (#12437). 

I found Jack Heinemann’s input (#12440) very enlightening in this context, as it describes the unexpected and unknown that can and will always be present, like the contamination of routine reagents with nucleic acids, or the contamination of commercial grade gene editing materials being contaminated e.g. with other guide fragments, thus allowing for other target sequences and unexpected incorporations.

It will require thorough and often long-term investigation, observation and characterisation as well as avoidance of assumptions to understand extra levels and sources of risks, other than the intended trait. It would indeed be a voluntary guidance material that could help with how to approach and assess these extra levels and sources.

As we are talking about genome editing of mammals, I would like to bring up another finding that brought to light an extra source of risk. Carrying out CRISPR/Cas experiments with cultured human and mouse cells, researchers found that genome editing is often counteracted by the cell’s own defences against DNA damage (Haapaniemi et al. 2018; Ihry et al. 2018). They also found that the likelihood of successful genome editing went up where the cell’s natural defences were low or not active at all. At the heart of this defence is the p53 tumour-suppressor protein, also known as the ‘Guardian of the Genome’. If this protein is doing its job, genome editing is largely guarded against, yet where the protein is mutated, genome editing becomes easy. This however raises concerns as to whether genome edited mammals may by design have a higher probability of developing cancer.



2. What could be the specific challenges to related to this issue?

For example they could be:

Unintended genetic changes due to the methodology and processes involved, including the unexpected, such as the examples given by Jack Heinemann or Christoph Then.

Unexpected outcomes - unrelated to the genetic changes made, such as the potential selection for lines weak in DNA damage protection (p53 mutant lines).
Increased stress burden of the genetically modified farm mammal due to higher performance rate and pressure, or due to ease of mass rearing, etc. This could for example link to reduced immune systems and higher disease propensity.

Impact on human health – I saw others have already reported on these, thus I refer to those for this topic.

Where are the intersections between agricultural use of land or use of facilities and that of the wider environment, and where or how could direct impacts occur and where and how could indirect impacts occur, and what might they be.  If LM goats for example are kept in the open, they are known to be highly agile – what would be the consequences of their escape, be that in Northern Europe, in Eastern Europe or in Africa. What if LM deer escapes?

Intensive animal rearing already places a high burden on the environment, including on groundwater and aquafers. Would this increase? Would there be for example more pollution, either by quantity or by intensity?


3. What are the specific issues concerning this topic?

(i)  Yes

(ii) Yes. Unless the farm animals are kept in tight containment -i.e. unescapable physical structures- animals can wander off, find gaps in fences, run off when scared or due to human failure. They can also be dispersed/moved due to extreme weather conditions, which can break down structures and fences and which are rapidly on the increase due to climate change.

Additionally, in many cases there would also be neighbouring farming populations, wild populations and relatives, depending on country, farming systems, ecosystem, type of mammal and possibly type of breed.

(iii) Yes, as above.

(iv) Yes.  I refer for this to the listings by other participants on this thread. 

I briefly would like to share about a particular development in sheep and goats, where genome editing is being used to create double-muscle herds (through the knockout of the myostatin gene). The aim, as pointed out by the authors, would be to shift meat production away from livestock and across to sheep and goats (Kalds et al. 2022). Such a shift would have strong implications, as such goats and sheep would be used widely.


4. To the best of my knowledge, there is no equivalent of a guidance available as would be needed for genome edited mammals in agriculture.


Again, thank you all for sharing all the different information, it makes for a very rewarding discussion.

With kind regards,
Ricarda


Resources:

Haapaniemi, E., Botla, S., Persson, J. et al. CRISPR–Cas9 genome editing induces a p53-mediated DNA damage response. Nat Med 24, 927–930 (2018). https://doi.org/10.1038/s41591-018-0049-z

Ihry, R. J., Worringer, K. A., Salick, M. R., Frias, E., Ho, D., Theriault, K., Kommineni, S., Chen, J., Sondey, M., Ye, C., Randhawa, R., Kulkarni, T., Yang, Z., McAllister, G., Russ, C., Reece-Hoyes, J., Forrester, W., Hoffman, G. R., Dolmetsch, R., & Kaykas, A. (2018). p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells. Nature medicine, 24(7), 939–946. https://doi.org/10.1038/s41591-018-0050-6

Kalds, P., Crispo, M., Li, C., Tesson, L., Anegón, I., Chen, Y., Wang, X., & Menchaca, A. (2022). Generation of Double-Muscled Sheep and Goats by CRISPR /Cas9-Mediated Knockout of the Myostatin Gene. Methods in molecular biology (Clifton, N.J.), 2495, 295–323. https://doi.org/10.1007/978-1-0716-2301-5_16

.

Dear All,
I am Valeria Giovannelli, and I work for the Italian Institute for Environmental Protection and Research. I have been working on issues related to Living Modified Organisms (LMOs) for nearly 20 years, including supporting my government in the assessment of environmental releases of GMOs within the EU and developing methodologies for Environmental Risk Assessment (ERA). Additionally, I ‘m following the CPB’ activities since 2014.

First of all I wish to thank Ana Laura Mello for moderating this second round of discussions and my thanks to all the colleagues for posting interesting and constructive comments and information answering to the specific questions of this forum.
I agree with the comment #12404, that solutions developed for LMOs will generally be suitable for LMOs developed by genome editing; in particular, the approaches proposed in existing guidance can and shall be applied (e.g. problem formulation, case by case and step wise approach).
I can agree with that comments on the fact that there are already some guidance that can be applied to assess GE or LM animal/mammals, but still we need to be sure that these guidance allow to take into the CPB objective, including transboundary movements when performing the ERA. Most of them were not developed to conduct an assessment from a biodiversity protection perspective, but rather from a human health standpoint.
As far as the specific answer to the questions proposed by the coordinators, I will repost some of those I made for the LM animals topic, indeed the references I shared are still valid for this topic as well.
On question 2: 2. What could be the specific challenges to related to this issue?

- Unintended epigenetic modifications: In mammals, genetic modifications can either be introduced into a zygote-stage embryo or into somatic cells in culture followed by transfer of the modified diploid nucleus into an enucleated oocyte using the process of somatic cell nuclear transfer. In both technologies, the resultant embryos are then transferred into recipient dams to generate a live-born animal. Each approach requires the use of assisted reproductive technologies (e.g. generation of preimplantation embryos, artificial activation of embryo development, in vitro culture of embryos) that can produce unintended epigenetic modifications irrespective of the genetic alterations brought about by the genetic modification itself (De Waal, E., W. Mak, S. Calhoun, P. Stein, T. Ord, C. Krapp, C. Coutifaris, R.M. Schultz, and M.S. Bartolomei. 2014. In vitro culture increases the frequency of stochastic epigenetic errors at imprinted genes in placental tissues from mouse concepti produced through assisted reproductive technologies. Biology of Reproduction - 90(2):22  DOI: 10.1095/biolreprod.113.114785 and De Waal, E., L.A. Vrooman, E. Fischer, T. Ord, M.A. Mainigi, C. Coutifaris, R.M. Schultz, and M.S. Bartolomei. 2015. The cumulative effect of assisted reproduction procedures on placental development and epigenetic perturbations in a mouse model. Human Molecular Genetics 24(24):6975-6985.) doi: 10.1093/hmg/ddv400.). The potential unintended epigenetic modifications shall be considered during ERA.  Methods to identify them and the related potential effects shall be further developed.
- Lack of standardized detection methods for unintended alterations:
For LM mammals various off-target detection methods are currently available, yet each has its own strengths and weaknesses (e.g., complex protocols, applicability across different cell types, associated costs, sensitivity, requirement of suitable controls, bias). Further empirical research is needed to benchmark and refine current
methods for genome sequencing and bioinformatic detection of unintended alterations. (National Academies of Sciences, Engineering, and Medicine. 2025. Heritable Genetic Modification in Food Animals. Washington, DC: The National Academies Press. https://doi.org/10.17226/27750)

On question 3(i): (i) Is there the potential to cause adverse effects on biodiversity, in particular those that are serious or irreversible, taking into account the urgent need to protect specific aspects of biodiversity, such as an endemic/rare species or a unique habitat or ecosystem, taking into account risks to human health and the value of biological diversity to indigenous peoples and local communities?

- A specific potential risk of disease-resistant LM livestock is the potential evolution of pathogens in both animal and human populations (Looi, F.Y., M.L. Baker, T. Townson, M. Richard, B. Novak, T.J. Doran, and K.R. Short. 2018. Creating disease resistant chickens: A viable solution to avian influenza? Viruses 10:561. https://doi.org/10.3390/v10100561). During ERA the hypothesis that pathogens might adapt to overcome resistance, potentially increasing their ability to infect new hosts, including wildlife and humans, or evade treatments should be analysed. Monitoring activities that combine disease surveillance in LM animals with wildlife monitoring to track pathogen changes and mitigate risks should be suggested (Gao, G.F. 2018. From “A”IV to “Z”IKV: Attacks from emerging and re-emerging pathogens. Cell 172(6):1157-1159, DOI: 10.1016/j.cell.2018.02.025; National Academies of Sciences, Engineering, and Medicine. 2025. Heritable Genetic Modification in Food Animals. Washington, DC: The National Academies Press. https://doi.org/10.17226/27750).


On question 3 (ii): ii) Is there the potential to have an introduction into the environment either deliberately or accidentally?
- To assess this issue the characteristics of the LM animal, considering also the associated management of the production systems, together with accessible ecosystem(s) (e.g. marine, fresh water, cultivated agricultural habitats, natural and semi-natural habitats, rural and urban areas) should be assessed in order to identify potential environmental exposure pathways.

Dear Participants,

Thank you kindly for your insights and your continued active engagement during the second week of discussions.

Week 2 of the Open-Ended Online Forum is now closed.

The online forum remains open for the Week 3 topics. Kindly refer to the ongoing discussions at https://bch.cbd.int/en/portals/risk-assessment/forum/week-3.

Best regards,

The Secretariat