Question 4: What existing guidelines, guidance documents or experiences developing guidance materials could be important to consider for the development of these additional voluntary guidance materials?

None. It should be used the Cartagena Protocol, Annex III and Codex Alimentarius, which contain the guidance to assess and evaluate LMOs.

--- Posted on behalf of Dr. Luciana Pimenta Ambrozevicius, Brazil ---

Dear Participants,

Some existing materials for risk assessment considering scientific evidence could be:
- Recommendation of ERA for gene drive applications for malaria vector control: https://doi.org/10.1186/s12936-022-04183-w
- A pathway for gene drive governance: https://doi.org/10.4269/ajtmh.19-0941
-WHO Guidance framework for testing genetically modified mosquitoes: https://apps.who.int/iris/bitstream/handle/10665/341370/9789240025233-eng.pdf?sequence=1&isAllowed=y

Thank you.

Best regards,
Luciana

Hello everybody, my name is Christoph Then and I am a member of ENSSER (The European Network of Scientists for Social and Environmental Responsibility) and representing Testbiotech (http://www.testbiotch.org) in this discussion. Testbiotech compiled recent information in a backgrounder for this forum https://www.testbiotech.org/node/3037. In our backgrounder, we give an overview on existing guidance material that should be used for the development of the additional guidance within this working group.

Guidelines for the export, shipment, import and release of biological control agents and other beneficial organisms. – International Standards for Phytosanitary Measures (ISPM 3) of the International Plant Protection Convention (IPPC) is also a useful resource to guide this process. https://www.fao.org/3/j5365e/j5365e.pdf

The release of biological control agents in South Africa follows guidance on ISPM 3 which requires:
1. sufficient characterization of the biological control agent or other beneficial organism to allow for its accurate identification, in general to the species level at minimum;
2. a summary of all available information on its origin, world distribution, biology, natural enemies, hyper parasites, and impact in its area of distribution
3. available information on host specificity (in particular, a list of confirmed hosts) of the biological control agent or beneficial organism and any potential hazards posed to non-target hosts
4. Description of natural enemies and contaminants of the agent and procedures required for their elimination from laboratory colonies. This includes, where appropriate, procedures to identify accurately and, if necessary, eliminate from the culture the host upon which the biological control agent or beneficial organism was cultured. Information on any phytosanitary measures taken prior to shipment should also be provided.

In South Africa the process of issuing a permit for release of a biological control agent requires the applicant to provide specific information on the target weed; the candidate biological control agent and the envisaged research; as well as a prediction on the potential impact of the biological control agent on the environment. Import permits for candidate biological control agents are issued by the Department of Agriculture, Land Reform and Rural Development (DALRRD) subject to the requirement that the candidate agents be confined to an approved quarantine facility. During that period the biology, behaviour and host range of the candidate agents are examined, together with any other aspects (e.g. impact on the target weed in the laboratory) necessary to convince the decision makers of their safety for release into the environment. A comprehensive report is then submitted to DALRRD, which incorporates the results of quarantine trials, and sometimes field surveys in the native range of the agents, as well as information obtained from the literature. Based on this report, the Bio-control Release application Review committee takes the decision whether or not to authorize the release of the biological control agent into the environment. Applications for released of biological control agents submitted in terms of the Agricultural Pest Act 36 of 1983 are reviewed by three independent reviewers, who provide recommendations to the review committee. Introduction of gene drive organisms may trigger other legislations in South Africa such as the Agricultural Pest Act.

Another useful resource is by Sabrina Kumschick et al. (2020) who present a framework on Risk Analysis for Alien Taxa (RAAT). It outlines a series of questions related to an alien taxon’s likelihood of invasion, realised and potential impacts, and options for management. The framework provides a structure for collating relevant data from the published literature to support a robust, transparent process to list alien taxa under legislative and regulatory requirements. The framework has been trialed in South Africa on a number of taxa.

https://doi.org/10.3897/neobiota.62.51031

Dear colleagues,

This is Hector Quemada. I'm a retired biosafety scientist with experience in risk assessment of LMOs, including those containing gene drives. I would like to add the following document to the list of guidance. It contains material ton risk assessment, among other things, that supplements the 2014 WHO guidance, with focus on mosquitoes containing gene drives. Thanks for the opportunity to contribute.

James S, Collins FH, Welkhoff PA, et al (2018) Pathway to Deployment of Gene Drive Mosquitoes as a Potential Biocontrol Tool for Elimination of Malaria in Sub-Saharan Africa: Recommendations of a Scientific Working Group. The American Journal of Tropical Medicine and Hygiene 98:1–49. https://doi.org/10.4269/ajtmh.18-0083 (https://www.ajtmh.org/view/journals/tpmd/98/6_Suppl/article-p1.xml)

Dear Colleagues,

I am Hector Quemada, retired biosafety scientist. I have commented on the online forum on Synthetic Biology last month.

As we think about the development of guidance for LMOs containing gene drives, especially mosquitoes, we should learn
from the experience gained during the development of the previous risk assessment guidance
(UNEP/CBD/BS/COP-MOP/8/8/Add.1). We know that many years were spent by an AHTEG to write the document, and an extensive
series of online forum discussions were conducted. There was also a period of testing and revision. In the end, the
COP-MOP did not endose the guidance. Thus, in my view, there was much effort and expense devoted to this process that
could have been put to better better use in serving the needs of the Parties.

The lessons learned from this process are well summarized in an analysis done by Hokanson KE (2019) When Policy Meets
Practice: The Dilemma for Guidance on Risk Assessment Under the Cartagena Protocol on Biosafety. Frontiers in
Bioengineering and Biotechnology 7:1–18. https://doi.org/10.3389/fbioe.2019.00082

If the AHTEG does not keep these lessons in mind, and avoids the mistakes committed during that effort, there is a risk
of repeating those mistakes and developing yet another guidance document that does not serve well the purposes of the
Convention on Biological Diversity, and hinders the successful implementation of the Cartagena Protocol. Thanks for the
opportunity to contribute to this discussion.

Good evening, my name is Heidi Mitchell, from the Office of the Gene Technology Regulator (OGTR) in Australia.
There are many helpful resources on how to perform risk assessment of GMOs which can be applied to gene drive organisms, including the Risk Analysis Framework used by the OGTR (https://www.ogtr.gov.au/sites/default/files/files/2021-07/risk_analysis_framework_raf_-_2009.pdf).
I agree with Luciana that the paper which was developed following a series of online workshops on gene drive applications for malaria vector control is a valuable resource (https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04183-w).

----Posted on behalf of Mr. Kamal Kumar Rai---

On behalf of IPLCs, it is highly appreciated and thank you so much for the document related to question number 4. Unknown impacts, adverse effects of the new and emerging, assumption failures, technological errors, alteration and other factors that could impacts Mother Nature, Sacred and Alive. if such an event occurs, a whole society will be adversely impacted. There is not clear responsible mechanism to take responsible and reflects will be devastating if the innovation release as such. There is high chances of other circumstances that harm for health, water, food systems and ecological functions links with natural environment, gene pollutions that impacts other continents. 

There is a lack of behavorial study of the new invention that plays a role on social change within and with other society of the species or target population in ecosystems, biological or genetical impacts. 

A holistic principle, regulatory and moratorium mechanism, recognize and respect the rights of Mother Nature for survival, social integration and customary systems of IPLCs and relationship could be key elements on the guidance.

Thanks with regards
Kamal Kumar Rai
IPLC

Hi, Dear participants.

My name is Galina Mozgova. I am the Head of the National Coordination Biosafety Centre of the Institute of Genetics and Cytology with experience in risk assessment, biologist with specialization in genetics. I also participate in the online forum on Synthetic Biology.

When conducting risk assessment, information about recipient organism or parental organism is very important. Good consensus documents could be a source of information on biological characteristics of the recipient organism or parental organisms, centres of origin and centres of genetic diversity, description of the habitat where the organisms may persist or proliferate, and other information for risk assessment. I think that OECD consensus documents on parental organisms are one of those good sources. Here is the link to the consensus document of the biology of mosquito https://www.oecd-ilibrary.org/docserver/9789264302235-en.pdf?expires=1681744318&id=id&accname=guest&checksum=C61B962C118FAF48E078F74188486308.

Best regards,
Galina

Dear all,

my name is Eder Toppa, I've been working for the Brazilian Ministry of Agriculture and Livestock for the past decade and currently I am also member of the National Biosafety Comission. I've attended the COP / MOP meetings held in Montréal last december.
Apologies for only writing now.

No gene drive organisms have been proposed for release yet; hence regulatory authorities have never evaluated a risk assessment for the release of gene drive mosquitoes (for field evaluation or use). However, it is possible to build from previous experiences with other genetically modified mosquitoes.

Specifics issues on Risk Assessment were already considered in the “Study on Risk Assessment Application of annex I of decision CP 9/13 to living modified organisms containing engineered gene drives”

It should also be complementary to existing materials outside of CBD, such as the body of expertise and analysis already developed in many countries, as well as efforts specifically focused on gene drive organisms already undertaken by other international organizations:

• WHO - Guidance framework for testing of genetically modified mosquitoes, second edition. Available at https://www.who.int/publications/i/item/9789240025233
• WHO - Ethics and vector-borne diseases: WHO guidance. Available at https://apps.who.int/iris/handle/10665/336075;
• NASEM - Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values. Available at https://nap.nationalacademies.org/catalog/23405/gene-drives-on-the-horizon-advancing-science-navigating-uncertainty-and;
• Persus Report - Study on Risk Assessment Application of annex I of decision CP 9/13 to living modified organisms containing engineered gene drives.  Available at https://bch.cbd.int/protocol/risk_assessment/cbd-19-001%20perseus%20report%20draft%20191219%20-%20final%20for%20posting.pdf;
• Malaria Journal - Recommendations for environmental risk assessment of gene drive applications for malaria vector control. Available at https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04183-w;
• Australian Academy of Science – Synthetic Gene Drives in Australia: Implications of Emerging Technologies. Available at https://www.science.org.au/files/userfiles/support/documents/gene-drives-discussion-paper-june2017.pdf;
• Australian Office of the Gene Technology Regulator - Regulatory requirements for contained research with GMOs containing engineered gene drives. Available at https://www.ogtr.gov.au/sites/default/files/files/2021-06/guidance_on_gene_drives.pdf;

Sincerely

Hello everybody, my name is Angela Lozan, PhD, I work for the National Office for Environmental Projects Implementation of the Ministry of Environment of Moldova.

I would suggest to follow the study provided by EFSA:
-  Engagement on risk assessment for gene drive mosquitoes by EFSA and Target Malaria, by
Sarah Hartley, Adam Kokotovich, Ian Devos, John Mumford available at https://www.sciencedirect.com/science/article/pii/S1462901123000424 
- Adequacy and sufficiency evaluation of existing EFSA guidelines for the molecular characterisation, environmental risk assessment and post‐market environmental monitoring of genetically modified insects containing engineered gene drives, available at https://www.efsa.europa.eu/en/efsajournal/pub/6297

WHO: GUIDANCE FRAMEWORK FOR TESTING GENETICALLY MODIFIED MOSQUITOES, file:///C:/Users/Angela%20Lozan/Desktop/9789240025233-eng.pdf

Springer. Regulatory and policy considerations for the implementation of gene drive-modified mosquitoes to prevent malaria transmission, by Stephanie L. James, Brinda Dass & Hector Quemada, 2023, https://link.springer.com/article/10.1007/s11248-023-00335-z

Malaria Journal. Recommendations for environmental risk assessment of gene drive applications for malaria vector control, byJohn B. Connolly at al. Connolly et al. Malaria Journal (2022), https://doi.org/10.1186/s12936-022-04183-w

Hi everybody,
Thanks again to the moderators and contributors for this discussion.

I thank a previous contributor for pointing to the use of current risk assessment guidance on non-gene drive LMO insects for assessing gene drives. While a relevant starting point, it is my view that these experiences are equally important in highlighting how current guidance may be insufficient in dealing with gene drive organisms, and do not take necessary consideration of the intended (and potentially unintended) traits of gene drives, for example their design to spread and persist in the environment. Even for LMO insects that were not designed to persist, these have since been shown by independent scientists to indeed have persisted following trials https://doi.org/10.1038/s41598-019-49660-6. Such a scenario has not been sufficiently considered by the risk assessments of non-gene drive LMO insects, including those highlighted by previous contributions (e.g. #11589), and must even more so be considered for gene drive organisms.

Recent discussions on criteria for potential field trial releases have also revealed that processes for selection of field trial sites are often subject to power relations, where vulnerable communities may be forced to accept such projects not because they want them but because of unequal power relations. This is the case when, for example, deprived areas are explicitly chosen as field trial sites. As such, I would like to echo previous comments by my colleague Lim Li Ching in the Q1 thread [#11593] on the need for meaningful public participation and consideration for socio-economic factors in decision-making for risk assessment.  It would also be important to obtain the free, prior and informed consent of potentially affected indigenous peoples’ and local communities, as highlighted by previous AHTEGs and COP decisions, and in line with international human rights norms, including the Mo’otz Kuxtal Voluntary Guidelines adopted by COP13.

Hello all,
As the author of the article cited by Dr. Eva Sirinathsinghji, Third World Network #11600, I would like to recommend caution in interpreting these results.
Editorial Expression of Concern: Transgenic Aedes aegypti Mosquitoes Transfer Genes into a Natural Population
Addendum to: Scientific Reports https://doi.org/10.1038/s41598-019-49660-6, published online 10 September 2019

Dear all,

Thank you very much for the interesting discussion so far. I am Naomi Kosmehl, from the Foundation of future farming/Save Our Seeds, Berlin – Germany.

We would like to point out to the analysis of Frieß et al. on gene drive models that could be used to assist risk assessment. The researchers found that neither the models were realistic nor could they address all potential adverse impacts on the environment (https://doi.org/10.1016/j.ecolmodel.2023.110285). Therefore, existing gene drive modeling should be redesigned to address the shortcomings identified by the authors and when such models are used for the guidance materials then only with outmost precaution.

A publication by Bauer-Pankus et al. examines risk assessment in regard to plants that can propagate in the environment (https://doi.org/10.1186/s12302-020-00301-0). The authors point out some shortcoming of current risk assessment and propose improvements that could guide the AHTEG.

As Annex I of decision CP-9/13 points out, the risk assessment for gene drive organisms should also take into consideration risks to “the value of biological diversity to indigenous peoples and local communities”. We would therefore like to draw attention to the amplitude of publications on technology assessment that go beyond risk assessment and thus might provide valuable contributions to assess risks to the “value of biological diversity”. An exemplary recommendation for technology assessment can be found here: https://assess.technology/how/.

----Posted on behalf of Mr. Kamal Kumar Rai---

On behalf of IPLCs, it is appreciated and thank you so much for the documents on Target Malaria. Also, we agree and still need to deeply understand and also clear guidance and safegard. For IPLCs capacity building is very important, it is not clear and unknown about the LMO mosquito containing engineered gene drives and the techniques. A guideline is very important to have dialogue between IPLCs, science and policy in a good and faith base.

impacts, adverse effects of the new and emerging, failures of the assumption, technological errors, alteration and other factors that could impact on Mother Nature, is Sacred and Alive. There is no clear responsible mechanism to take responsibility and reflection will be devastating if the innovation is going to be released as such. There are high chances of other circumstances that harm to health, water, food systems and ecological functions link with the natural environment, gene pollution that impacts other continents. 

There is a lack of behavioral study of the new invention such as the gene drive mosquito that plays a role in social change within and with other societies of the species or target population in ecosystems, biological and adverse effects on gene or genetic erosion.

Step by step approach and holistic principle, regulatory and moratorium mechanism, recognize and respect the rights of Mother Nature for survival, social-cultural, knowledge integration and customary systems of IPLCs and relationship could be key elements.

Socio economic consideration, Free, Prior and Informed Consent, Full and effective participation of IPLCs, women, youth and Girls could be additional elements for the guideline.

Thanks with regards
Kamal Kumar Rai
IPLC

Dear Colleagues
Some useful materials for risk assessment Gene drive / mosquitoes

Adolfi A., Gantz V.M., Jasinskiene N., Lee H.F., Hwang K., Terradas G., Bulger E.A., Ramaiah A.,
Bennett J.D., Emerson J.J., Marshall J.M., Bier E., James A.A. (2020) Efficient population
modification gene-drive rescue system in the malaria mosquito Anopheles stephensi. Nat Commun
11(1): 5553. https://doi.org/10.1038/s41467-020-19426-0

Barrett L.G., Legros M., Kumaran N., Glassop D., Raghu S., Gardiner D.M. (2019) Gene drives in
plants: opportunities and challenges for weed control and engineered resilience. Proc Biol Sci
86(1911): 20191515. https://doi.org/10.1098/rspb.2019.1515


Carballar-Lejarazú R., Ogaugwu C., Tushar T., Kelsey A., Pham T.B., Murphy J., Schmidt H., Lee
Y., Lanzaro G.C., James A.A. (2020) Next-generation gene drive for population modification of the
malaria vector mosquito, Anopheles gambiae. PNAS 117(37): 22805-22814.
https://doi.org/10.1073/pnas.2010214117


Champer J., Kim I., Champer S.E., Clark A.G., Messer P.W. (2021) Suppression gene drive in
continuous space can result in unstable persistence of both drive and wild-type alleles. Mol Ecol 30
(4): 1086–1101. https://doi.org/10.1111/mec.15788

Connolly J.B., Mumford J.D., Fuchs S., Turner G., Beech C., North A.R., Burt A. (2021) Systematic
identification of plausible pathways to potential harm via problem formulation for investigational
releases of a population suppression gene drive to control the human malaria vector Anopheles
gambiae in West Africa. Malaria J 20: 170. https://doi.org/10.1186/s12936-021-03674-6

Connolly J.B., Romeis J., Devos Y., Glandorf D.C.M., Turner G., Coulibaly M.B. (2023) Gene
drive in species complexes: defining target organisms. Trends Biotechnol 41: 154-164.
https://doi.org/10.1016/j.tibtech.2022.06.013

CSS (Critical Scientists Switzerland) (2019) Gene Drives - A report on their science, applications,
social aspects, ethics and regulations. https://genedrives.ch/report

Devos Y., Mumford J.D., Bonsall M.B., Camargo A.M., Firbank L.G., Glandorf D.C.M., Nogué F.,
Paraskevopoulos K. Wimmer, E. A. (2021) Potential use of gene drive modified insects against
disease vectors, agricultural pests and invasive species poses new challenges for risk assessment.
Crit Rev Biotechnol 42(2): 254-270. https://doi.org/10.1080/07388551.2021.1933891

Dolezel M., Simon S., Otto M., Engelhard M., Züghard W. (2019) Gene drive organisms -
implications for the environment and nature conservation: a joint report of the EPA/ENCA Interest
Group on Risk Assessment and Monitoring of GMOs. Umweltbundesamt - Environmental Agency
Austria (ed.). Vienna (REP-0704).
https://www.umweltbundesamt.at/fileadmin/site/publikationen/rep0705.pdf

EFSA (2013) Guidance on the environmental risk assessment of genetically modified animals.
EFSA J 11(5): 3200. https://doi.org/10.2903/j.efsa.2013.3200

EFSA (2020) Scientific Opinion on the adequacy and sufficiency evaluation of existing EFSA
guidelines for the molecular characterisation, environmental risk assessment and post-market
environmental monitoring of genetically modified insects containing engineered gene drives. EFSA
J 18(11): 6297. https://doi.org/10.2903/j.efsa.2020.6297

Evans B.R., Kotsakiozi P., Costa-da-Silva A.L., Ioshino R.S., Garziera L., Pedrosa M.C., Malavasi
A., Virginio J.F., Capurro M.L., Powell J.R. (2019) Transgenic Aedes aegypti mosquitoes transfer
genes into a natural population. Sci Rep 9: 13047. https://doi.org/10.1038/s41598-019-49660-6

Frieß J.L., von Gleich A., Giese B. (2019) Gene drives as a new quality in GMO releases – a
comparative technology characterization. PeerJ, 7, e6793. https://doi.org/10/ggfwhb

Frieß J.L., Lalyer C.R., Giese B., Simon S., Otto M. (2023) Review of gene drive modelling and
implications for risk assessment of gene drive organisms. Ecol Modell 478: 110285.
https://doi.org/10.1016/j.ecolmodel.2023.110285

von Gleich A. & Schröder W. (eds.) (2020) Gene Drives at Tipping Points. Springer Book,
https://doi.org/10.1007/978-3-030-38934-5

Waltz E. (2021) First genetically modified mosquitoes released in the United States. Nature
593(7858): 175-176. https://doi.org/10.1038/d41586-021-01186-6

O.A.El-kawy

Gutemberg D. Sousa - Technical Assistent of National Biosafety Commitiee
With regard to the use of genetically modified mosquitoes, I am forwarding a publication with interesting data on the success of the Brazilian experience in the use of this technology to control diseases vectored by aedes

https://www.nature.com/articles/d41586-023-01266-9?WT.ec_id=NATURE-202304&sap-outbound-id=C4DE550A6EB57C4559824F649CDAA44CC997E76C

My name is Ernst Wimmer and I am Professor for Developmental Biology at the Georg-August-University Göttingen, Germany. My research includes applied approaches in insect biotechnology to establish modern genetic pest management methods. For the Open-ended Online Forum, I was nominated by the German Federal Ministry of Education and Research.

I would like to point out the EFSA activity regarding Gene Drive Modified Insects, which summarized not only the different strategies on Gene Drive approaches but also other transgenic approaches in regards to biotechnological improvement of the Sterile Insect Technique (SIT).

Devos, Y., Mumford, J.D., Bonsall, M.B., Camargo, A.M., Firbank, L.G., Glandorf, D.C.M., Nogué, F., Paraskevopoulos, K., Wimmer, E.A. (2021). Potential use of gene drive modified insects against disease vectors, agricultural pests, and invasive species poses new challenges for risk assessment. Critical Reviews in Biotechnology, DOI: 10.1080/07388551.2021.1933891.

Devos, Y., Bonsall, M.B., Firbank, L.G., Mumford, J., Nogué, F., Wimmer, E.A. (2020). Gene Drive-Modified Organisms: Developing Practical Risk Assessment Guidance. Trends in Biotechnology: 39, 853-856.

EFSA GMO Panel (EFSA Panel on Genetically Modified Organisms), Naegeli H, Bresson J-L, Dalmay T, Dewhurst IC, Epstein MM, Guerche P, Hejatko J, Moreno FJ, Mullins E, Nogue F, Rostoks N, Sanchez Serrano JJ, Savoini G, Veromann E, Veronesi F, Bonsall MB, Mumford J, Wimmer EA, Devos Y, Paraskevopoulos K and Firbank LG (2020). Scientific Opinion on the adequacy and suffciency evaluation of existing EFSA guidelines for the molecular characterisation, environmental risk assessment and post-market environmental monitoring of genetically modified insects containing engineered gene drives. EFSA Journal 2020;18:6297, 90 pp.

EFSA  (European  Food  Safety  Authority), Devos Y, Bonsall MB,  Nogué F, Paraskevopoulos K, Wimmer EA and Firbank LG (2020). Outcome of a public consultation on the draft adequacy  and  sufficiency  evaluation  of  existing  EFSA  guidelines  for  the  molecular  characterisation, environmental  risk  assessment  and  post-market  environmental  monitoring  of  genetically  modified insects  containing  engineered  gene  drives. EFSA  Supporting  publication  2020:EN-1939. 318 pp.

Dear colleagues,

I would also like to mention the report from the Environmental Agency in Austria and the German Federal Agency for Nature Conservation which has specific considerations for environmental risk assessment and monitoring:

Dolezel M., Simon S., Otto M., Engelhard M., Züghard W. (2019) Gene drive organisms -
implications for the environment and nature conservation: a joint report of the EPA/ENCA Interest
Group on Risk Assessment and Monitoring of GMOs. Umweltbundesamt - Environmental Agency
Austria (ed.). Vienna (REP-0704).
https://www.umweltbundesamt.at/fileadmin/site/publikationen/rep0705.pdf

And the EFSA opinion on genetically modified insects containing engineered gene drives in he context of current EFSA risk assessment and monitoring guidelines. In this opinion, EFSA highlights areas in which further guidance should be developed as these are not covered by current guidelines.

EFSA (2020) Scientific Opinion on the adequacy and sufficiency evaluation of existing EFSA
guidelines for the molecular characterisation, environmental risk assessment and post-market
environmental monitoring of genetically modified insects containing engineered gene drives. EFSA
J 18(11): 6297. https://doi.org/10.2903/j.efsa.2020.6297

I would also like to mention that while most of the existing guidance, including the EFSA opinion, are focused on insects alone. However, many other systems and organisms have been described as potential applications of gene-drives to which such guidance might not fully apply.

Thank you once again for the opportunity to share information.

Best regards,
Sarah

Dear colleagues,

In addition to guidelines and guidance documents also other relevant sources should be considered for the development on voluntary guidance materials on risk assessment of LMOs containing engineered gene drives. Examples are:

Dolezel, M.; Lüthi, C. & Gaugitsch, H. (2020): Beyond limits -  the pitfalls of global gene drives for environmental risk assessment in the European Union. BioRisk 15: 1-29. Doi: 10.3897/biorisk.15.49297. https://biorisk.pensoft.net/article/49297/

A joint technical report of the EPA/ENCA Interest Group on Risk Assessment and Monitoring on GMOs (2019): Gene drive organisms. Implications for the environment and nature conservation. https://www.umweltbundesamt.at/fileadmin/site/publikationen/rep0705.pdf

A report provided by ENSSER, CSS & VDW (2019): Gene Drives. A report on their science, applications, social aspects, ethics and regulations. https://ensser.org/publications/2019-publications/gene-drives-a-report-on-their-science-applications-social-aspects-ethics-and-regulations/

Best regards,
Anita

Dear participants,

My name is Samson Simon, I work for the German Federal Agency for Nature Conservation (BfN) as a biosafety expert.

I would like to reflect on guidance material produced by other national and international institutions, like those developed by the WHO. This material is of importance for this process, however it should be kept in mind that other material might have been developed with different primary protection goals in mind. It will be crucial to tailor the CBD guidance material on LMOs containing engineered gene drives to the protection goals of the CBD.

I would also like to echo previous posts about existing work on guidance material by Anita Greiter (#11618), Sarah Agapito-Tenfen (#11615), Ossama AbdelKawy (#11609) and others. This is a small list of documents (including own work) for consideration that might contribute to the development of additional voluntary guidance material on LMOs containing engineered gene drives.

Dolezel, M.; Lüthi, C. & Gaugitsch, H. (2020): Beyond limits - the pitfalls of global gene drives for environmental risk assessment in the European Union. BioRisk 15: 1-29. Doi: 10.3897/biorisk.15.49297. https://biorisk.pensoft.net/article/49297/

A joint technical report of the EPA/ENCA Interest Group on Risk Assessment and Monitoring on GMOs (2019): Gene drive organisms. Implications for the environment and nature conservation. https://www.umweltbundesamt.at/fileadmin/site/publikationen/rep0705.pdf

Frieß J.L., Lalyer C.R., Giese B., Simon S., Otto M. (2023) Review of gene drive modelling and implications for risk assessment of gene drive organisms. Ecol Modell 478: 110285. https://doi.org/10.1016/j.ecolmodel.2023.110285

Courtier-Orgogozo, V. Danchin, A. Gouyon, P.-H. Boëte, C. (2020) Evaluating the probability of CRISPR-based gene drive contaminating another species Evo. App. https://doi.org/10.1111/eva.12939

Verma, P.; Reeves, R. G.; Simon, S.; Otto, M.; Gokhale, C. S. (2023): The Effect of Mating Complexity on Gene Drive Dynamics. In: The American Naturalist 201 (1), DOI: 10.1086/722157.

Simon, S.; Otto, M.; Engelhard, M. (2018): Synthetic gene drive: between continuity and novelty. Crucial differences between gene drive and genetically modified organisms require an adapted risk assessment for their use. In: EMBO reports (5). DOI: 10.15252/embr.201845760.

Dears,

We wanted to draw your attention to the activities on the risk assessment of gene drive modified insects (GDMIs) conducted by the European Food Safety Authority (EFSA) on behalf of the Directorate-General for Health and Food Safety (DG SANTE) of the European Commission.

To support the European Union in its work on gene drive modified organisms (GDMOs) under the CPB/CBD, EFSA assessed, through a problem formulation exercise, whether: (1) “market” environmental releases of GDMOs could pose risks and potential novel hazards to human and animal health and the environment; (2) the scientific considerations given in its previously published guidance for the risk assessment of GMOs are adequate and sufficient for GDMOs (EFSA, 2012, 2013); and (3) there is a need for updated guidance in relation to the previous published guidance (EFSA, 2012, 2013). EFSA focused its activities on disease-transmitting insects, primarily mosquitoes, as they represent the most likely cases of GDMOs for release in the near future, but also considered agricultural insect pests and non-native invasive insects.

Based on a review of relevant information reported in the scientific literature and progress in developing gene drive modified insects (GDMIs), and assessment of the considerations given in EFSA (2012, 2013, 2020b,c), EFSA concluded that its guidelines for genetically modified insects (GMIs) that do not contain an engineered gene drive provide an appropriate basis for the risk assessment of GDMIs, but should be more specific to address the challenges that GDMI releases may pose. While the risk assessment of GDMIs can build on the existing framework for GMIs, it was concluded that there are specific areas within the molecular characterisation, environmental risk assessment and post-release monitoring, where further guidance is needed. These areas include among other aspects: the genetic and phenotypic stability of the transgenic construct; assessment of unintended on-target and off-target activity of site-directed nucleases and their consequences; consideration of receiving environments; engineered gene drive spread and persistence in the field; knowledge on the functional role of the target organism and potential cross-compatible species in the various ecosystems that may be encountered; definition of relevant comparators; model design, quality assurance, validation and interpretation; and post-release monitoring (EFSA, 2020a).

Note that EFSA recently launched the call for tender “OC/EFSA/NIF/2023/01 – Preparatory Work for the Development of Risk Assessment Guidance for Gene Drive Modified Insects”. The aim of the call is to gather and assess the necessary information to fill the gaps in existing risk assessment guidelines for GMIs previously identified by EFSA (EFSA, 2020) and provide recommendations on aspects to consider for the potential development of additional guidance for the risk assessment of GDMIs for deliberate release into the environment. This call focuses on the use of engineered gene drives in disease-transmitting insects, primarily mosquitoes, agricultural insect pests and non-native invasive insects for deliberate release into the environment. The outcome of the proposed activities would allow EFSA to better prepare for future challenges in risk assessment of GDMIs. The project has an overall duration of two years and is divided into five broad objectives.

-Objective 1 – Review relevant case studies and their risks to human, animal and environmental health
-Objective 2 – Review molecular designs (including implications for molecular characterisation and risk assessment)
-Objective 3 – Review comparators (including implications for environmental risk assessment)
-Objective 4 – Review factors affecting engineered gene drive dynamics, including models designed to investigate such dynamics (including implications for environmental risk assessment and post-market environmental monitoring)
-Objective 5 – Review monitoring approaches (including implications for post-market environmental monitoring)

More information about the call for tender is available at https://etendering.ted.europa.eu/cft/cft-display.html?cftId=13511.

Relevant references:

-2020c – Adequacy and sufficiency evaluation of existing EFSA guidelines for the molecular characterisation, environmental risk assessment and post-market environmental monitoring of genetically modified insects containing engineered gene drives – EFSA Journal – http://dx.doi.org/10.2903/j.efsa.2020.6297
-2021 – Potential use of gene drive modified insects against disease vectors, agricultural pests and invasive species poses new challenges for risk assessment – Critical Reviews in Biotechnology – http://dx.doi.org/10.1080/07388551.2021.1933891
-2020b – Outcome of a public consultation on the draft adequacy and sufficiency evaluation of existing EFSA guidelines for the molecular characterisation, environmental risk assessment and post-market environmental monitoring of genetically modified insects containing engineered gene drives – EFSA Supporting Publications – https://doi.org/10.2903/sp.efsa.2020.EN-1939
-2020a – Stakeholder workshop “Problem formulation for the environmental risk assessment of gene drive modified insects” (15 May 2019, Brussels) – EFSA Supporting Publications – https://doi.org/10.2903/sp.efsa.2020.EN-1819
-2013 – Guidance on the environmental risk assessment (ERA) of GM animals – EFSA Journal – https://doi.org/10.2903/j.efsa.2013.3200
-2012 – Guidance for the risk assessment of food and feed derived from GM animals and on related animal health and welfare aspects – EFSA Journal – https://doi.org/10.2903/j.efsa.2012.2501

We hope the information shared will be helpful.

Wishing you all the best,

Yann Devos (Senior scientific officer in the Chief Scientist Office of the European Food Safety Authority (EFSA)) and Alexandre Huchelmann (Policy officer in the Biotechnology Unit of the Directorate-General for Health and Food Safety (DG SANTE) of the European Commission)

In the post #1600 Dr. Eva Sirinathsinghj mentions a study by Evans et al. 2019 (https://www.nature.com/articles/s41598-019-49660-6) reporting the transfer of genes into a natural populations of Aedes aegypti mosquitoes following the releases of transgenic mosquitoes in Brazil. First I think it is important here to recall that these transgenic mosquitoes are partially sterile as a fraction (about 4% of them) is expected to survive even in the absence of tetracycline (see Phuc et al. 2007 doi: 10.1186/1741-7007-5-11) leaving transgenic mosquitoes alive. As a reply to the post #1600, Dr Capurro recommended great caution in interpreting the results of Evans et al. 2019 and mentions an Editorial Express of concern publish in Scientific Reports https://www.nature.com/articles/s41598-019-49660-6.

I think this is important to bring to the attention of this forum that this editorial concern alters of undermines the publication by Evans et al. that was peer-reviewed. Moreover it provides an ambiguous text that is related to the conclusion and does not make it clear that the methods, the analysis and the data quality are not in question.Thus, the editor’s note does not:

- Identify clearly whether the nature of concern is based focused on subjective matters of interpretation (and that anything like misconduct or honest errors are not an issue in this case).
- Indicate which aspects of the paper are problematic (i.e., which specific data or conclusions are invalid).
- Indicate what factors ultimately led to the publication of the Editorial expression of concern

Moreover the paper has been strongly criticised by Oxitec in her response on its own website (see : https://www.oxitec.com/en/news/oxitec-response-scientific-reports-article) that also claims a successful project in Jacobina. Such results about a success need also to be taken with great caution as while they were presented with a 81% decrease of the Aedes aegypti population base on ovitrap indices (see Carvalho et al. 2015 : https://doi.org/10.1371/journal.pntd.0003864) a re-analysis of the available data (Boëte & Reeves, 2016. Lancet Global Health see: https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(16)00084-X/fulltext and https://www.thelancet.com/cms/10.1016/S2214-109X(16)00084-X/attachment/f3edbd7a-ab19-4ded-941b-ad013acc6932/mmc1.pdf ) highlights that for both control and release areas the ovitrap index decreased between the beginning and the end of the trial, leading then to a lower real efficacy of the transgenic release at reducing the mosquito population in this release.

Regards,

Christophe Boëte

Dear participants

I´m Carolina Villafañe from The Ministry of Environment of Colombia, and I am in charge of Biosafety issues and, The Cartagena Protocol.

The voluntary guidance materials should be oriented by the next elements:

1. What types of gene drives are available in the market or will be available soon in the market.
2. From those gene drives identified in step one, which ones are designed to respond to priorities or necessities in areas (health, environment, industry, agriculture, etc.) that may affect the objectives of conservation and sustainable use of biodiversity of the Convention.
3. Then, it is necessary to do an analysis of in what kind of organisms the gene drives identified in step 2 are used, that means what are de host organisms.
4. Once identified what types of host organisms could represent the most risk for the conservation and sustainable use of biodiversity, taking into account human and agrosystems health, the voluntary guides should be focused on these gene drives-organisms systems.
5. An analysis of the scientific and technical aspects to be developed for each gene drive-organism system for the risk assessment method should be carried out.

Sincere regards.

There is nothing wrong with the data presented in Evans et al. 2019, however, the title is misleading and the interpretations and speculations are farfetched and not supported by the data.

In this study they analyzed the population at a time there was still release going on and they actively disregarded transgenitically marked individuals, as they could have been released ones.

Therefore, the study only shows that you get introgression of parts of the released genome into the genome of the local population at least during the time of release, which is an obvious thing, when the released individuals are not 100% sterile. This however has nothing to do with the released individuals being trangenic or not. This does also happen in any classical SIT approach without transgenes in them. Therefore the actual data of that manuscript show a scientific triviality and putting the word "transgenic" into the title is maybe catchy but completely misleading, as it has nothing to do with the released insects being transgenic or not.

What would actually have been interesting, is a similar study but about two years after the stop of the release and then really analyze whether the transgenes stayed in the population or what of the introduced genomic parts were kept, or whether all this would be elimited over time and the population would mostly go back to its original composition. In case introduced genomic parts would stay, it would be interesting to see what are the genes that are kept and then potentially identify the reasons for that.

This would be an insightful story. The data published in Evans et al. 2019 are a scientific triviality with a misleading title and farfetched speculations. This is the reason why actually an official co-author of the paper is vehemently pointing out the shortcomings and misleading character of this paper!

Best regards,
Ernst Wimmer
Professor for Developmental Biology at the Georg-August-University Göttingen, Germany.
My research includes applied approaches in insect biotechnology to establish modern genetic pest management methods.
For the Open-ended Online Forum , I was nominated by the German Federal Ministry of Education and Research.

Dear All,

One critical issue that has received little attention in this forum is that related to biosafety/biosecurity, especially as to how gene-drives could be hijacked by bad actors.

In #11632 Mrs Carolina Villafañe pointed to something that I believe should also be in this threat.

The question is if gene drives could be regarded as a "double-use technology or material." There is no doubt that gene-drives, just as many other forms of modern biotechnologies, ARE dual-use. And, whichever definition one may use, they are certainly also of the "dual-use-of-concern" category (DURC). In essence, this means that while the technology aims for good outcomes, it could be misused by bad actors to create harm, and in this case, this could be far reaching, including the entire ecosystem.

As an advisor to ENISA (The European Union Agency for Cybersecurity), I have been doing quite some work in this regard, more generally, related to DURC potentials in the life-sciences; as a multidisciplinary researcher at the interface between cybertechnology and nature (Ph.D. in Biomedical Sciences, Ph.D. in Mathematics, “Habilitation” in Cryptography and Data Security), as I recently pointed out also during the recent past forum on Synthetic Biology, this sector is one of the most vulnerable areas of the entire bioeconomy.

A brief summary of the URGENT needs to better understand how the convergence of biology with  computers, networked systems, and AI, could maliciously exploit the inherent DURC aspects of the biotech sector, can be found at https://www.enisa.europa.eu/publications/research-and-innovation-brief/@@download/fullReport.

We are currently working on a much more in-depth publication that will be published soon. I would encourage everyone to please check out ENISA’s updates regarding “cyber-biosecurity” in particular. In this forthcoming document, we are identifying critical gaps that DO apply to gene-drives as well, and how these, either inadvertently or deliberately could, because of their inherent DURC nature, create substantial harm, including “systemic,” and how, resp. if/in which context, new mitigation measures may, or may not, help solve these largely unexplored risks and dangers.

I am sorry this final ENISA document is not ready. But it will be finished soon.

A few years ago, I published some work as to how genetically modified plants could be misused to cause harm, and also, why these dangers may not have received the attention this urgent topic deserves (https://www.frontiersin.org/articles/10.3389/fbioe.2019.00121/full). Because of the unavoidable GAP created between the computerized technology and biology, I posit that many, if not all of these dangers apply analogously to gene-drives as well. With the latter, of course, the adverse effects may have even more far-reaching potentials (i.e. as bioweapons). And, given that numerous aspects of the underlying technologies are still very much unknown/debated, this knowledge gap creates a significant risk potential for unintended mishaps and misuse as well.

Best wishes,
Siguna

Dear participants,

My name is Váleri Vásquez, I am a PhD student at the University of California Berkeley whose research includes the computational modeling of gene drive modified mosquitoes. It is gratifying to note the wealth of existing high-quality guidance material available to the AHTEG.

I note the comment by Dr. Yann Devos (#11629), which outlines the EFSA call for tender “OC/EFSA/NIF/2023/01 – Preparatory Work for the Development of Risk Assessment Guidance for Gene Drive Modified Insects”, a two-year project of which the fourth of five objectives is to “review factors affecting engineered gene drive dynamics, including models designed to investigate such dynamics (including implications for environmental risk assessment and post-market environmental monitoring).”

This nod to the importance of understanding the biotic and abiotic factors that may affect extra-laboratory gene drive dynamics, and the relevance of models to such work, is supported by the recently published “Review of gene drive modelling and implications for risk assessment of gene drive organisms”(https://doi.org/10.1016/j.ecolmodel.2023.110285). This paper – already cited by many in this Forum – speaks to the need for models that are designed from the outset to study specific risk-related questions, and in particular potential ecological consequences.

To augment the compendium of modeling-relevant peer-reviewed materials germane to developing voluntary guidance, I include the following which may serve to underpin specific proposals and applications. While the third was published prior to the 2020 AHTEG, I highlight it as one example of a model-based approach to accounting for ecological impacts, including indirect ones:
• The Effect of Mating Complexity on Gene Drive Dynamics (January 2023): https://doi.org/10.1086/722157
• Gene Drive Dynamics in Natural Populations: The Importance of Density Dependence, Space, and Sex (November 2020): https://doi.org/10.1146/annurev-ecolsys-031120-101013
• Genetic engineering to eradicate invasive mice on islands: modeling the efficiency and ecological impacts (December 2016): https://doi.org/10.1002/ecs2.1589

In addition to the above, I echo the points made by several colleagues in this forum particularly those by Mr. Hector Quemada (#11563) who advises learning from the experiences gained during the AHTEG’s development of previous risk assessment guidance namely UNEP/CBD/BS/COP-MOP/8/8/Add.1 and document summarizing lessons learned from this process (https://doi.org/10.3389/fbioe.2019.00082).

Likewise, I concur with the suggestion by Dr. Heidi Mitchell (#11564) in support of Dr. Luciana Pimenta Ambrozevicius (#11547) that the paper “Recommendations for environmental risk assessment of gene drive applications for malaria vector control” – which was written following a series of online workshops on gene drive applications for malaria vector control – furnishes a  valuable resource (https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04183-w).

Thank you,
Váleri N. Vásquez

At the time of my writing this, previous posts had identified 55 documents that contain guidance or describe experiences developing guidance material. Two of these documents are highlighted on four occasions: Connolly et al. (2022) and EFSA (European Food Safety Authority) et al. (2020), whilst another three – Dolezel et al. (2019), Frieß et al. (2023) and WHO-TDR & FNIH (2021) – are cited on three occasions. Another seven are cited twice and the remaining 43 documents are identified once (Table Q4).

There is clearly a lot of existing guidance material that participants within this forum deem relevant, and no doubt there are other relevant documents that have not already been listed , such as M. Benedict et al. (2008) and M. Q. Benedict et al. (2018). Such a large body of literature could prove daunting to individuals seeking guidance, and I wonder therefore if forums such as this can assist by identifying a smaller set of key existing documents.

In any event, I believe it is important that any further guidance address specific gaps and add value to the information contained within the existing literature, and note the similar sentiments expressed by #11563; #11575, #11603 and #11621. Moreover, further guidance should be developed and promoted in a fashion that promotes capacity building: in many jurisdictions the lack of capacity to conduct a risk assessment is a more pressing issue than the availability of relevant guidance.

REFERENCES
Connolly, John B., John D. Mumford, Debora C. M. Glandorf, Sarah Hartley, Owen T. Lewis, Sam Weiss Evans, Geoff Turner, et al. 2022. “Recommendations for Environmental Risk Assessment of Gene Drive Applications for Malaria Vector Control.” Malaria Journal 21 (1). https://doi.org/10.1186/s12936-022-04183-w.

EFSA (European Food Safety Authority), Yann Devos, Michael B. Bonsall, Fabien Nogué, Konstantinos Paraskevopoulos, Ernst A. Wimmer, and Leslie G. Firbank. 2020. “Outcome of a public consultation on the draft adequacy and sufficiency evaluation of existing EFSA guidelines for the molecular characterisation, environmental risk assessment and post-market environmental monitoring of genetically modified insects containing engineered gene drives.” EFSA Supporting Publications 17 (11): 1939E. https://doi.org/https://doi.org/10.2903/sp.efsa.2020.EN-1939.

Dolezel, M., S. Simon, M. Otto, M. Engelhar, and W. Züghard. 2019. “Gene drive organisms - implications for the environment and nature conservation: A joint report of the EPA/ENCA InterestGroup on Risk Assessment and Monitoring of GMOs.” Umweltbundesamt - Environmental Agency Austria (ed.). Vienna (REP-0704).

Frieß, Johannes L., Carina R. Lalyer, Bernd Giese, Samson Simon, and Mathias Otto. 2023. “Review of Gene Drive Modelling and Implications for Risk Assessment of Gene Drive Organisms.” Ecological Modelling 478 (April): 110285. https://doi.org/10.1016/j.ecolmodel.2023.110285.

WHO-TDR & FNIH. 2021. “Guidance Framework for Testing of Genetically Modified Mosquitoes, Second Edition.” World Health Organisation, Geneva, Switzerland.

Benedict, M. Q., J. D. Charlwood, L. C. Harrington, L. P. Lounibos, W. K. Reisen, and W. J. Tabachnick. 2018. “Guidance for Evaluating the Safety of Experimental Releases of Mosquitoes, Emphasizing Mark-Release-Recapture Techniques.” Vector Borne and Zoonotic Diseases 18 (1): 39–48. https://doi.org/10.1089/vbz.2017.2152.

Benedict, M., P. D’Abbs, S. Dobson, M. Gottlieb, L. Harrington, S. Higgs, A. A. James, et al. 2008. “Guidance for Contained Field Trials of Vector Mosquitoes Engineered to Contain a Gene Drive System: Recommendations of a Scientific Working Group.” Vector Borne and Zoonotic Diseases 8: 127–66. https://doi.org/10.1089/vbz.2007.0273.

APPENDIX
Table Q4: Summary of citations identified by participants in relation to Question 4 during the open-ended online forum on risk assessment risk assessment of living modified organisms containing engineered gene drives
Reference Count
Connolly2022 4
EFSA2020 4
Dolezel2019 3
Friess2023 3
WTF2021 3
Devos2021 2
Dolezel2020 2
Evans2019 2
GMO2020 2
Hokanson2019 2
Smets2020 2
Verma2023 2
AAS2017 1
Backus2016 1
BauerPanskus2020 1
Connolly2021 1
CourtierOrgogozo2020 1
Devos2021a 1
Dhole2020 1
EFSA2020a 1
EPGMO2013 1
EPGMOAHW2012 1
EPGMOG2020 1
FAO2005 1
Hartley2023 1
James2018 1
James2023 1
Kumschick2020 1
Lenharo2023 1
NASEM2016 1
OECD2018 1
OGTR2009 1
Simon2018 1
Switzerland2019 1
Toe2022 1
WHO2020 1

I would like to thank everyone who has helped to identify a number of valuable perspectives, insights, and resources.

I am a multidisciplinary independent researcher nominated by ENSSER (The European Network of Scientists for Social and Environmental Responsibility), and relevant to this threat, I am currently an advisor to ENISA (The European Union Agency for Cybersecurity) on safety/security issues at the interface of computerized technology and biology. These concern the technologies underlying gene-drives also, and their implementation.

Several in this group (most recently #11643) argued there are still gaps in risk assessment and the existing literature which do have to be identified.
Of note, other disciplines have independent risk-assessment rules, practices, and criteria. In particular, the information and communication technology (ICT) community has extensive experience in this regard. Noting that gene drives cannot be realized without computerized technology, the computer-biology interface and resulting risks (cyber-bio-security) must not be ignored, even from a legal perspective. This will be even more important with the future approval of the proposed CRA (https://digital-strategy.ec.europa.eu/en/library/cyber-resilience-act).

For example, the cyber-security disciplines are asked to secure the cyber-components underlying synthetic biology - and in many applications are mandated to furnish rigorous and effective cyber-bio risk assessment and mitigation measures. The latter category concerns especially those with potential systemic impact/adverse effects as may be the case with gene-drives. Via the computer overlaps with biology, stakeholders at the bioscience side, including those working on gene-drives and related synbio applications, will have to provide clear information to the ICT community as to where exactly unresolved risks and gaps reside.

In the context of risk assessment pertaining to gene-drives, some in this forum have noted that these are often tied to benefits (cost-benefit scenarios) and have described some of the resulting challenges that result from bringing the factor of “benefits” into the discussion (as in particular described by Jack Heinemann  #11638).

Importantly, to the ICT community, a “risk” refers to the possibility or potential occurrence of events or incidents that could compromise the interests or interfere with the realization of objectives for an organization. In biotechnology the objectives relate to the preservation or improvement of life (see ISO/IEC 15408 https://www.iso.org/obp/ui/#iso:std:iso-iec:15408:-1:ed-3:v2:en).

As such, it is critical to assess “risks” of gene-drives independently of expected/potential benefits (ie., the framework must not be about risk-benefit analyses). From the perspective of gaps, the ICT community is clear: whenever there is a risk, it needs to be accounted for. I suggest the same conception should also apply to the risk-assessment of gene-drives.

If we cannot provide an exact identification of risk-potentials (independent from expected benefits), we may endanger the safe and secure development of combined cyber-biological systems and implementations (including technologies underlying gene-drives), even though they are increasingly required by several agencies; thereby, this will undoubtedly also increase vulnerabilities related to both unintended adverse effects (including accidents) as well as intentional forms of mal-/misuse, exploiting the inherent dual-use features of gene-drives (e.g. as bioweapons with potentially systemic consequences).

For various aspects (risk identification etc) of such interdisciplinary risk-assessment strategies that are necessary because of the way gene-drives are realized via modern technologies (more broadly known as cyber-bio-security, aka cybersecurity in the life sciences) please see the following:

https://www.enisa.europa.eu/publications/research-and-innovation-brief/@@download/fullReport

forthcoming (the full and extended version of the above): The European Union Agency for Cybersecurity's "Cybersecurity Research and Innovation Brief" on "Cybersecurity in Life Sciences" by Siguna Mueller and Marco Barros Lourenco (ENISA): ISBN: 978-92-9204-632-3 DOI: 10.2824/835532 

https://www.frontiersin.org/research-topics/8353/mapping-the-cyberbiosecurity-enterprise (a total of 16 articles, with some more specific on various related topics in synthetic biology)

https://doi.org/10.1016/j.bsheal.2020.09.007

https://www.frontiersin.org/articles/10.3389/fbioe.2019.00121/full (which points to challenges rather than solutions pertaining to GM plants through the perspective of safety/security and ICT interfaces)

Thank you.
Siguna

----Posted on behalf of Mr. Kamal Kumar Rai---

There are many uncertainties of the new and emerging innovation, technological errors that cause adverse impacts to Mother Nature, ecological functions, food chain and systems of each niche outbreak, environmental crisis and survival challenges. IPLCs want to have more collaboration, cooperation, transparencies, responsibilities and regulatory mechanisms in respect the objectives and spirit of the Convention.  It is being an important inclusive mechanism and promote the convention’s Article 8G to maintain, regulate, manage or control, explicitly the risks associated with the use and release of living modified organisms including LMOs containing engineering gene drives resulting from biotechnology or modern biotechnology which are likely to have adverse environmental impacts that could affect the conservation, customary sustainable use of IPLCs. 

Traditional, Indigenous and local knowledge, practices, innovations of IPLCs are vital complimentary as indigenous sciences for LMO, LMO containing engineering gene drive Risks Assessment and Risks Management and full and effective participation of IPLCs at all level integrating the Article 8(j), self-determination of indigenous peoples, socio-economic consideration and incorporate the outcomes of the Risks Assessment ATHEG 2020, within the objectives of the convention. 

The IPLCs observations, experiences on ground indigenous epistemologies, worldviews, cultures and traditions. Indigenous wholistic theory and ideas can play an important role for Risk Assessment and Risks management, full and effective participation of IPLCs on the program of work, activities and socio-cultural appropriate capacity building, where IPLCs can contribute in a love, respect, courage, honesty, wisdom, humanity and truth

Thanks with regards
Kamal Kumar Rai
IPLC

Dear Colleagues,

Thank you for very engaging discussions. My name is Josephine Amedu, working for the National Biosafety Management Agency, Nigeria and a member of a Technical Working Group serving the West African Intergrated Vector Management (WA-IVM) platform as well as a contributor to the 2nd Edition Gene Drive Report of the AU High Level Panel on Emerging Technologies (APET). The WA-IVM platform, launched in 2018, provides a foundation for the regulation of gene drives at a regional level and fosters collaboration and expertise in controlling vector-borne diseases like malaria, using gene drives. The platform has developed a set of technical guidelines to provide guidance to scientists in the West African region, undertaking research activities with gene drive modified mosquitoes and regulators who may be reviewing such activities. These guidelines are expected to be launched any moment now and published by the African Union Development Agency (AUDA-NEPAD). The AU High Level APET Report: Gene Drives for Malaria Control and Elimination in Africa (https://www.nepad.org/publication/gene-drives-malaria-control-and-elimination-africa) examines the use of gene drives for the control and elimination of malaria in Africa and further provides recommendations with regard to policy regulatory systems.
Put together, these documents underpins the need for harmonisation of guidance policies and proper coordination of approaches towards the regulation of gene drives of mosquitoes.

Thank you for the opportunity to share my thoughts.

Kindly yours,
Josephine.

Questions have been raised in this forum as to the role of modelling of gene drives in relation to risk assessment   Modelling can give many insights regarding gene drives, such as at large spatial scales e.g North et al https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-020-00834-z
used simulation modelling to understand factors affecting spread of gene drive over a one million-square kilometre scale.  Modelling can also be used to identify parameters that are the most sensitive to change by using statistical sensitivity analysis as in the MGDriveE framework [https://github.com/cran/MGDrivE] mentioned by Dr Capurro in Question 1 #11649.

Modelling can also be used to define characteristics of gene drives in mosquitoes in the development pipeline through a Target Product Profile (TPP). A paper authored by Marshall et al https://www.frontiersin.org/articles/10.3389/fitd.2022.828876/full  discusses the insights models can provide and the importance of reliable predictions, discussed by a wide range of stakeholders.  This paper also indicates that models may be helpful in informing risk, remediation and cost dimensions for mosquito gene drives, as gene drive mosquitoes may be more cost-effective than other control methodologies due to their potential effectiveness.

I’d also like to draw attention to the presentation of “ Application of quantitative ecological risk assessment to the release of gene drive “ by Dr Wayne Landis, given as part of the GeneConvene seminar series. [https://www.youtube.com/watch?v=HZ-5BlS9vC8]

Dear Colleagues:

I am Bob Friedman with the J. Craig Venter Institute.  I introduced myself earlier in a post to Question 1 [#11599].  I would like to pick up on a point amply illustrated by Keith Hayes [#11641, #11642, #11643]: the number of existing guidance documents and publications of direct relevance for developing guidance documents is quite large.  Hayes suggests that a key role for online forums such as the one we have engaged in for the past two weeks is to “assist by identifying a smaller set of key existing documents”. 

I will expand on this notion and suggest something along these lines for the additional voluntary guidance materials to be developed by the next AHTEG.  In my view, what would be extremely helpful to potential users would be for the AHTEG to perform a meta-analysis of the current top-tier guidance materials, identifying one or more examples of best practices for each of the specific elements important for a case-specific risk assessment of a field trial or full deployment of a gene drive organism.  No individual existing guidance document is strongest in all areas.  But each has its strengths.

This “meta-guidance” would identify examples of current best practices for, e.g., identifying pathways to harm, when and how to employ ecological models, incorporating stakeholder views, evaluating the potential efficacy of the intervention, etc. It would be, in essence, guidance for making best use of the existing guidance. Of course, best practice can always be improved, and suggestions for doing so would also be quite helpful, where appropriate.  But given that it is neither practical nor wise for the AHTEG to develop new voluntary guidance materials from scratch, this “meta-guidance” document of examples of best practice would both add value today and could be easily updated as needed as both risk assessment practices and gene drive technologies advance in the future.

Regards,
Bob Friedman

Good morning. I am Sharmila Buldewo, Scientific Officer at the Food Technology Laboratory, Ministry of Agro-Industry and Food Security, Mauritius. First of all, thank you to the CBD Secretariat and the Moderator, Dr Luciana Ambrozevicius for the excellent work done so far. Secondly, thank you to all the participants. The contributions have been very insightful and enriching.

Mauritius is still in the early stage in the implementation of risk assessment and risk assessment of  modified organisms.  Given that the topic is under scrutiny, a precautionary approach would be privileged. I think that it is important to encourage the participation of all stakeholders including the public or representatives of the public, as from the beginning of the process of risk assessment and management. This will enhance trust as the process would be transparent and to consider all possible risks particularly if there is a lack of background information to simulate the actual effects post implementation/marketing/release of the modified organisms.

I found the  "Guidelines for the safety assessment of novel foods" from the Food Directorate of Canada a very good start.

Dear colleagues,

My name is Geoff Hosack and I am a research scientist at the Commonwealth Scientific and Industrial Research Organisation (CSIRO) in Australia. My research area is probabilistic ecological risk assessment, including risk assessments for transgenic strains of self-limiting, non-gene drive mosquitoes developed by Target Malaria.

I have read with interest the many posts pointing to the existence of helpful guidance for gene drive risk assessments, and also those that have provided suggestions on how the practice of risk assessments can be improved through the construction of better guidelines. I wonder if the following (not exhaustive) recommendations may also assist the development of guidelines specific to gene drive risk assessments:

- PRISMA and extensions for reviews and meta-analyses (http://prisma-statement.org/)
- Preregistration of studies (https://doi.org/10.1038/s41562-022-01497-2)
- FAIR data principles for transparency, reproducibility, and reusability (https://force11.org/info/the-fair-data-principles/)

References to recommendations such as the above, where appropriate, may help improve accessibility and understanding of risk assessments but would not replace additional guidance specific to gene drive risk assessment. For example, EFSA (2020) reviewed previous guidance for GM risk assessments (EFSA 2013) from the perspective of gene drive strategies (#11629). Several areas that were identified by EFSA (2020), where improved guidance could assist gene drive risk assessments, incorporate statistical analysis, for example: mathematical modelling and analysis, monitoring and surveillance.

Identifying specific elements of guidance in the above three technical/statistical areas is an interesting challenge. For example, EFSA (2020) distinguishes case-specific monitoring versus general surveillance. The differences between these two areas could be expected to lead to substantively different guidance for the development of statistical designs relevant to case specific gene drive risk assessments. Some level of technicality should be expected in this guidance. But if guidance is overly prescriptive then methods that are not ultimately fit for purpose to the case in question may be unnecessarily prioritised. On the other hand, if guidance is too open-ended then it will be difficult for risk analysts and regulators to interpret, implement and evaluate the guidance. Although the challenge is there, the inclusion of guidance that somehow strikes the right balance will surely help improve the integrity of case specific gene drive risk assessments.

Many thanks to the participants for the generous contribution of their expertise to this forum.

Kind regards,

Geoff

Dear colleagues, following up from Bob Friedman’s post (11656), I thought it might be interesting to see what the top cited documents in the forum were as of the time I posted (apologies haven’t time to add the additional references since then) - the result is in the table below. Top citations as follows:

• WHO-TDR & FNIH (2021) (7 votes)
• Connolly et al. (2022), Devos et al. (2021), EFSA (European Food Safety Authority) et al. (2020) (5 votes)
• Connolly et al. (2021), Connolly et al. (2023), EFSA GMO Panel (EFSA Panel on Genetically Modified Organisms) et al. (2020), Frieß et al. (2023), Organisation for European Cooperation and Development (2018) (4 votes)

Appreciate that simple vote counting exercises such as this are likely to be inadequate but it may provide a starting point for a subsequent discussion.

References:
WHO-TDR & FNIH. 2021. “Guidance Framework for Testing of Genetically Modified Mosquitoes, Second Edition.” World Health Organisation, Geneva, Switzerland.

Connolly, John B., John D. Mumford, Debora C. M. Glandorf, Sarah Hartley, Owen T. Lewis, Sam Weiss Evans, Geoff Turner, et al. 2022. “Recommendations for Environmental Risk Assessment of Gene Drive Applications for Malaria Vector Control.” Malaria Journal 21 (1). https://doi.org/10.1186/s12936-022-04183-w.

Devos, Yann, John D. Mumford, Michael B. Bonsall, Ana M. Camargo, Leslie G. Firbank, Debora C. M. Glandorf, Fabien Nogué, Konstantinos Paraskevopoulos, and Ernst A. Wimmer. 2021. “Potential Use of Gene Drive Modified Insects Against Disease Vectors, Agricultural Pests and Invasive Species Poses New Challenges for Risk Assessment.” Critical Reviews in Biotechnology 42 (2): 254–70. https://doi.org/10.1080/07388551.2021.1933891.

EFSA (European Food Safety Authority), Yann Devos, Michael B. Bonsall, Fabien Nogué, Konstantinos Paraskevopoulos, Ernst A. Wimmer, and Leslie G. Firbank. 2020. “Outcome of a public consultation on the draft adequacy and sufficiency evaluation of existing EFSA guidelines for the molecular characterisation, environmental risk assessment and post-market environmental monitoring of genetically modified insects containing engineered gene drives.” EFSA Supporting Publications 17 (11): 1939E. https://doi.org/https://doi.org/10.2903/sp.efsa.2020.EN-1939.

Connolly, John B., John D. Mumford, Silke Fuchs, Geoff Turner, Camilla Beech, Ace R. North, and Austin Burt. 2021. “Systematic Identification of Plausible Pathways to Potential Harm via Problem Formulation for Investigational Releases of a Population Suppression Gene Drive to Control the Human Malaria Vector Anopheles Gambiae in West Africa.” Malaria Journal 20 (March): 170. https://doi.org/10.1186/s12936-021-03674-6.

Connolly, John B., Jörg Romeis, Yann Devos, Debora C. M. Glandorf, Geoff Turner, and Mamadou B. Coulibaly. 2023. “Gene Drive in Species Complexes: Defining Target Organisms.” Trends in Biotechnology 41 (2): 154–64. https://doi.org/10.1016/j.tibtech.2022.06.013.

EFSA GMO Panel (EFSA Panel on Genetically Modified Organisms), Hanspeter Naegeli, Jean-Louis Bresson, Tamas Dalmay, Ian C. Dewhurst, Michelle M. Epstein, Philippe Guerche, et al. 2020. “Adequacy and sufficiency evaluation of existing EFSA guidelines for the molecular characterisation, environmental risk assessment and post-market environmental monitoring of genetically modified insects containing engineered gene drives.” EFSA Journal 18 (11): e06297. https://doi.org/https://doi.org/10.2903/j.efsa.2020.6297.

Frieß, Johannes L., Carina R. Lalyer, Bernd Giese, Samson Simon, and Mathias Otto. 2023. “Review of Gene Drive Modelling and Implications for Risk Assessment of Gene Drive Organisms.” Ecological Modelling 478 (April): 110285. https://doi.org/10.1016/j.ecolmodel.2023.110285.

Organisation for European Cooperation and Development. 2018. Safety Assessment of Transgenic Organisms in the Environment, Volume 8. OECD. https://doi.org/10.1787/9789264302235-en.

Simple vote count of documents in the online forum as midnight 23rd April AEST
Var1 Freq
WTF2021 7
Connolly2022 5
Devos2021 5
EFSA2020 5
Connolly2021 4
Connolly2023 4
EPGMOG2020 4
Friess2023 4
OECD2018 4
Devos2021a 3
Dolezel2019 3
GMO2020 3
Verma2023 3
Benevenuto2023 2
CourtierOrgogozo2020 2
Dolezel2020 2
Evans2019 2
Hartley2023 2
Hay2021 2
Hokanson2019 2
Huestis2019 2
James2023 2
NASEM2016 2
Simon2018 2
Smets2020 2
Switzerland2019 2
AAS2017 1
AGC2017 1
Backus2016 1
Barron2019 1
Bartlow2019 1
BauerPanskus2020 1
Besansky2003 1
Bier2021 1
Bruehl2020 1
Coetzee2013 1
Collins2018 1
Connolly2023a 1
Costantini2009 1
Dabire2013 1
Dainty2021 1
Devos2022 1
Dhole2020 1
EFSA2020a 1
EPGMO2013 1
EPGMOAHW2012 1
EPPPPR2014 1
FAO2005 1
Foster1995 1
Fouet2012 1
Franklinos2019 1
Friess2019 1
Glandorf2017 1
Hayes2018 1
Iwamura2020 1
James2018 1
James2020 1
James2023a 1
Kaiser2021 1
Kumschick2020 1
Lenharo2023 1
Li2020 1
Li2022 1
Madzokere2020 1
Mnzava2022 1
Munhenga2011 1
Nelson2009 1
OGTR2009 1
Overcash2022 1
Peterson2022 1
Poulin2012 1
Price2015 1
Raban2020 1
Sanogo2020 1
SCBD2020 1
Spinner2022 1
Teem2019 1
Theissinger2019 1
Tjaden2018 1
Toe2022 1
Tonui2022 1
Wells2022 1
White1971 1
White1974 1
WHO2020 1
WVCAG2022 1

Dear participants,

Following the discussion on guidance material, the need to understand modelling approaches remains pivotal in order to enable risk assessment of LMOs containing engineered gene drives.

However, LMOs containing engineered gene drives might behave in unintuitive ways, which is one of the reasons modelling approaches might be so useful, also in risk assessment. There is a manifold of modelling approaches for a manifold of engineered gene drive mechanisms, some with overlapping concepts but differing nomenclature.

In this regard, I would like to draw your attention to the following publication (Verma et al. 2021 doi: 10.1186/s12862-021-01881-y), that describes and categorizes gene drive mechanisms using common vocabulary. It simplifies the parameters for modelling spread and recovers some of the models published in the past.
This work comes with an online tool (DrMxR – Drive Mixer, https://pverma.shinyapps.io/DrMxR/), that allows interested stakeholders to explore gene drive dynamics and experience the effects of parameter spaces. While the concept is explained in the publication, an additional user manual is available with the online tool. Please note that this tool is for research and educational purposes only.

Thank you very much for this interesting online forum.

Best regards
Samson Simon (German Federal Agency for nature conservation/biosafety unit)

Literature: Verma, P., Reeves, R.G. & Gokhale, C.S. A common gene drive language eases regulatory process and eco-evolutionary extensions. BMC Ecol Evo 21, 156 (2021). https://doi.org/10.1186/s12862-021-01881-y

Dear colleagues,
My name is Heidi Mitchell from the Office of the Gene Technology Regulator in Australia. I would like to support the approach suggested by Bob Friedman (#11656) and Keith Hayes (#11643) to analyse the existing 'top tier' guidance and use this as the basis for the additional voluntary guidance materials. I was reminded of a quotation by Frank H. Westheimer, an American chemist "Why spend a day in the library when you can learn the same thing by working in the laboratory for a month?" which could be applied here to suggest not going back to first principles but building on existing knowledge.

Dear all,

I am Geoff Turner, working with the Target Malaria project supporting regulatory and risk analysis processes for our various project partners. It is encouraging to see such an engaging dialogue on this topic.

I would like to take this opportunity to comment on the point made by Mr. Kamal Kumar Rai in response #11606 around the suggestion that “Socio economic consideration, Free, Prior and Informed Consent, Full and effective participation of IPLCs, women, youth and Girls” be considered as elements of voluntary guidance materials, under the specific topic of risk assessment, which is the subject of this forum.

Mr Kumar references very important considerations which warrant a robust, systematic and structured analysis, which should form part of the decision-making process for project proponents, potentially impacted communities, as well as government decision makers at key project stages.    To me this speaks explicitly to the work of the AHTEG on Socio-Economic Considerations in biosafety decision making in consideration of Article 26 of the Cartagena Protocol, and should not be an add-on to the risk assessment process under discussion here.  Incorporating these considerations into voluntary guidance on risk assessment could in fact dilute the assessment of potential impacts in the socioeconomic and cultural domains, as the environmental risk assessment framework in the current context may not provide the most appropriate scope.  There are specific methodologies and a wealth of global experiences in assessing socioeconomic, health, and cultural considerations, which can be drawn upon, and have been in evolution under Environmental and Social Impact Assessment (ESIA)  frameworks since well before the Cartagena protocol was even conceived.  Guidance for ESIA and associated environmental and social management systems are well developed and have been applied in many sectors for decades.  The International Association for Impact Assessment  (https://www.iaia.org/ ) provides a starting point for familiarisation with ESIA processes. 

The tools of Environmental and Social impact assessment  (ESIA)  provide an opportunity to undertake a structured approach to the assessment of socio-economic considerations to inform decision making and improve project environmental and social performance.  In the emerging area of genetic approaches to vector control, precedent is lacking, but use of ESIA in decision making is being explored by the Target Malaria project in the context of its developmental pathway.

Please refer to the following publication for some reflection on the topic, and how the work of the AHTEG on Socio-Economic Considerations in biosafety decision making could better take into account existing evidence-based ESIA processes to proactively seek views of potentially impacted parties, and provide a valuable reference point in developing governance models for socioeconomic considerations in biosafety decision making.

Turner, Geoff (2023).  Assessment tools for decision making for area wide malaria vector control using gene-drive approaches – perspectives on evaluation of socio-economic considerations. Modern Biotechnology in Integrated Plant Production. IOBC-WPRS Bulletin Vol. 163, pp. 88-95

(Please note this publication is behind a paywall at this time due to constraints of the hosting organisation IOBC, but has been uploaded here)

Thank you for the opportunity to participate.

Geoff Turner

----Posted on behalf of Mr. Kamal Kumar Rai---

On behalf of the IPLC world view, it is heartily thank you so much Geoff Tumer for the great support.

Thanks with regards
Kamal Kumar Rai

My name is Marja Ruohonen-Lehto, and I work as a Senior Adviser at the Finnish Environment Institute. I have a PhD in genetics and have worked on biosafety issues for more than 25 years. I have been a member of previous AHTEGs on risk assessment and risk management and have participated in the Cartagena COP-MOP negotiations since 2006.

I would like to support the following interventions, in particular: # 11598, # 11613, # 11615, # 11618, # 11625, # 11653, # 11663 and # 11664. I am very supportive of the idea that all existing guidance is carefully analysed and used in the development of additional voluntary guidance materials as per the COP-MOP 10 decision. However, I would be hesitant to “rank” any existing guidelines or guidance based on how many times they were referred to in the interventions during our discussions. No individual intervention ranked any of the information they included. All information should be equally analysed and taken into account.

Thanks a lot again, very useful and informative.

In addition and in support of Dr Ruohonen-Lehto, I am not sure that the list includes all those who only posted doi information within their posts and therefore may be incomplete.