In their report, the 2019 AHTEG on Synthetic Biology identified an non-exhaustive list of trends that could inform the process for broad and regular horizon scanning, monitoring and assessment. Thus, to inform the work of the multidisciplinary AHTEG, participants are kindly requested to provide information on the trends identified, their relevance and when applications are likely to be available under these areas.

The following questions are meant to guide the discussion. Participants are encouraged to consider them when intervening, for their potential  to facilitate a systematic analysis of the information.

b) What could be potential positive and the potential negative impacts vis-à-vis the three objectives of the Convention arising from such applications?

----Posted on behalf of Dr. Martin Cannell---

Welcome to the Open-Ended Online Forum on Synthetic Biology!

My name is Martin Cannell, I am a regulatory scientist with a background in plant molecular biology and biotechnology. I have extensive experience working on the risk assessment and regulatory requirements for living modified organisms both within the laboratory and relating to environmental releases.

I am honoured to serve as moderator of this forum and as such, I intend to provide support and guidance to the discussions as they progress.

When planning your intervention, please note that if you would like to respond to a post, we would like to encourage you to reply directly to that post. This will also facilitate the understanding of others. In addition, when posting information, kindly provide the URL, the DOI or use the attachment function.

As a kind reminder, discussions will close on 17:00 (5pm) EST on Friday, 31 March 2023.

We thank you for your participation in this forum, and we look forward to an interesting discussion.

Sincere regards,
Dr. Martin Cannell

Sintayehu A Mekonnen is a plant geneticist research officer working at the Ethiopian Biodiversity Institute, Ethiopia. My research work focuses on crop genetic resources exploration, collection, characterization and evaluation for desirable traits by employing morphological, biochemical and molecular tools. I am also a committee member of Open Forum for Agricultural Biotechnology /OFAB/ Ethiopia.

The topic of synthetic biology is not the current research agenda in Ethiopia. So we do not have on going research activities or for commercialization of synbio tech. However there is an urgent need to start synbio technologies in Ethiopia since the technologies have many applications in various fields most importantly medical sciences, sustainable agriculture, biofuel etc , Recognizant of these, Ethiopian Bio and Emerging Technology Institute (BETin) have started to develop a national genome editing communication strategy with the support from The Centre of Excellence in Science, Technology, and Innovation of the African Union Development Agency-NEPAD (AUDA-NEPAD).

Ethiopia is not the producer of synbio technologies so far. We do not have synbio technologies currently and its’ associated either negative or positive impacts of the three CBD objectives. However, we may import synbio technologies like that of other import commodities, which may have some negative impacts to our rich biodiversity since Ethiopia is center and diversity of some crops.

Tēnā koutou katoa, my name is Dan Tompkins and I am the Science Director | Kaiwhakahaere matua – Pūtaiao for the New Zealand crown-owned company Predator Free 2050 Limited, and an Honorary Professor at the University of Otago, both in Aotearoa New Zealand.

I would like to offer that the IUCNs technical report ‘Synthetic biology applications intended for conservation benefit’ published in 2019 (https://www.iucn.org/resources/issues-brief/synthetic-biology-and-its-implications-biodiversity-conservation), alongside other similarly robust syntheses, provides a good foundation for the debate of this question to build on.

The report objectively assesses both negative and positive potential impacts of synthetic biology applications across four classes (ecological and human effects, and application and ethical issues), with an updated overview published last year (https://www.sciencedirect.com/science/article/pii/S2589004222016959).

Among others, example potential costs were that synthetic biology applications could become invasive, impact on rural livelihoods, be coopted for private gain or military use, or there being moral hazards of not preventing extinctions.

Among others, example potential benefits were the prevention of extinctions, the creation of new collaborations and new jobs, the addressing of intractable conservation issues, and a reversal of the sense of conservation loss.

I am Ma. Lorelie U. Agbagala, Philippines’ BCH National Focal Point. Following the suggestion of Dr. Dan Tompkins from New Zealand, I visited the report made by Macfarlane et.al., titled “Direct and indirect impacts of synthetic biology on biodiversity conservation”. I agree with him that it provides a good foundation for this discussion.
The report made an objective review of synthetic biology applications and its direct and indirect impacts on biodiversity conservation. They next discussed particular environmental governance challenges posed by synthetic biology and concluded by emphasizing the importance of case-by-case decision-making for synthetic biology applications of relevance to biodiversity conservation.

The take away message of the study is that conservation implications of synthetic biology applications should be considered on a case-by-case basis depending on the evidence for the positive and/or negative impacts they are likely to have on any given conservation objective. The fact that one application may be beneficial or detrimental in a certain social, political, economic, and ecological context does not mean that the same technology would have the same impacts in another context. Lumping synthetic biology applications might therefore mask the complexity of the issues.
Very best wishes.

In regard to the protection of biodiversity and its sustainable usage, we discuss some risks in our recent backgrounder we compiled on the horizon scanning of Synbio Organisms (https://www.testbiotech.org/node/3036). We also provide our findings on applications of SynBio organisms in nature protection in the context of the report from the IUCN as mentioned (https://www.testbiotech.org/node/2802).

In summary, the risks for disruption of ecological networks are dependent on the receiving environment, the traits, the species involved, the exposure as well as the potential interactions between the Synbio Organisms.

I am Professor Frederic Ngezahayo, plant geneticist at Higher Normal School of Burundi "Ecole Normale Supérieure du Burundi"
My research work focuses on plant moelcular epigenetics. I am also the Director of the Center for Science Research and Professional Development.

I have the same point of view as Sintayehu A Mekonnen. Indeed, the topic of synthetic biology is not the current research agenda in Burundi. Thus, there is no ongoing research activities or for commercialization of synbio tech. However, we are in urgent need to start synbio technologies in Burundi since the technologies have many applications in various fields most importantly medical sciences, sustainable agriculture, biodiversity conservation, etc.

But we are very limited in research, and then first of all, we need to build capacities in terms of human ressources (sensitization through workshops and courses, or other opportunities) to get more familial with Synbio technology, and in laboratories and their equipment, prior to any research project in Synthetic biology.

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.

About the potential positive and potential negative impacts of Synbio vis-à-vis the three objectives of the Convention, as with all scientific advances and approaches, it depends on the intended use, the risk evaluation results, and the ethical considerations on the application of a specific development. For example, developments that lead to species population control as a conservation strategy could have more negative impacts than positive of it,  for the objective of the Convention related to the conservation of biodiversity because today it is not possible to estimate with a low level of uncertainty the real dynamic of those genes into the wild. On the other hand, the Synbio products that solve climate problems like carbon fixation, or green energy solutions would be a positive impact on both sustainable use and conservation.

Concerning Benefit sharing derived from the use of genetic resources, Synbio will represent a key challenge because of the data governance and intellectual property rights, and possibly Synbio will be out of the scope of Access to genetic resources.

Sincere regards

With regard to potential positive or negative impacts of synbio applications discussed in topic 1a:

LMO microorganisms (relevant to trends 1, 2 and 3):
The increasing complexity of GM virus applications, particularly novel applications such as spreadable ‘vaccine’ viruses and Horizontal Environmental Genetic Alteration Agents (HEGAAs), are raising the degree of complexity and lack of knowledge of both intended and unintended releases, posing significant challenges to risk assessment. Moreover, the irreversibility and potential global spread could lead to transboundary movements well beyond the target area of release.  (See Greiter, A., Eckerstorfer, M. F., Miklau, M., Heissenberger, A., Engelhard, M., & Simon, S. (2022). Synthetic Biology. Scan the Horizon for Impacts on Biodiversity).
Such projects raise concerns regarding the high level of risk and uncertainty associated with the release of unrecallable, contagious viruses with the ability for rapid population spread and modification within a single generation (Lentzos et al., 2022 https://doi.org/10.1126/science.abo1980). The levels of uncertainty regarding viral evolution, ability to spill-over into non-target species, along with lack of controllability or recallability warrants immediate and urgent oversight into any potential future releases. To date, vaccine developers have, for safety reasons, developed vaccine platforms that are not capable of spreading (either inactivated viruses, or viral vectors with their replication ability removed) in order to improve safety profiles. These GM ‘vaccine’ virus projects could arguably be described as ‘re-gain of function’ viral experiments where such safety features are being reversed.

There are also questionable benefits of GM vaccine projects that ought to be considered. For example, GM virus ‘vaccines’ for rabies are being researched, yet effective vaccines are readily available. How such controversial projects may impact other vital public health programs and relationships with the public is also a relevant consideration.

Various GM bacterial or fungal applications e.g. to modify microbiomes, wild bacterial communities, or soil microbes raise a number of biosafety implications with potential adverse negative impacts on biodiversity with particular concerns around controllability and spread. GM bacteria may rapidly proliferate and persist, with unknown implications. Contamination of foods with GM microorganisms intended for contained use, including those carrying antibiotic resistance genes, have recently been detected in food products https://doi.org/10.1016/j.foodcont.2021.108665. Microbial species play various vital roles in ecosystems that include mediating soil chemistry e.g. soil carbon levels, supporting plant and tree defence, cross-kingdom communication, for example. Microorganisms also act in concert with other microbial species and host organisms in ways not fully understood, in symbiotic relationships with other species as well as host organisms. How perturbing complex partnerships networks within microbial communities and/or their host organisms will impact wider environmental or host organism’s health is highly uncertain.

Gene drive mosquitoes (relevant to trends 1, 2 and 3):
Gene drive mosquitoes raise a number of risks to biodiversity and human health. Unintended harms of gene drives, including for example, changes to pathogenicity or vector competence, or the potential for pathogen resistance to evolve to modification drives designed to block transmission, are difficult if not impossible to fully assess prior to release. These risks are compounded by the current lack of methods to fully recall gene drives and restore populations back to wild-type. The potential use of recently developed anti-CRISPR mosquitoes are not sufficient in this regard. This method of mitigation will only inactivate gene drive mechanisms but not remove transgenes and revert organisms back to wild-type.
Questions also need to be raised over potential efficacy limitations in reducing mosquito numbers and disease burden, with evidence from modelling data suggesting that suppression drives are unlikely to eliminate populations but result in mixed populations and more complex ‘chaser’ dynamics whereby local elimination would result in gaps in populations and wild-type rebounds to fill the localised empty niches. Other efficacy problems such as genetic instability or resistance development are also potentially hindering development, as well as the potential for self-limiting drives to indeed behave like self-sustaining versions. How this may impact public health goals is currently highly uncertain.
The move to technologies for health applications raises socio-economic considerations, including potentially promoting a focus on narrow biomedical interventions and singular diseases, often over the development of wider healthcare infrastructure and increased access. Excessive focus on technical interventions has the potential to result in unintended harms as a result of healthcare opportunity costs, and should thus be considered, especially when substantial question marks over their efficacy remain, as raised above.

Trend 4 on increasing sophistication of genetic modification techniques:
The advancement of techniques designed to increase the scope of species that can be modified by e.g. genome editing, as well as methods to deliver genome editing machinery that circumvent the need for tissue culturing or current transformation methods all have the potential to increase the scale of intervention. The continuing advancement in genome editing technologies, along with others (e.g., external RNA-based products, gene drive technologies, etc. that are moving engineering tools directly into the field) are increasing the magnitude and scale of human intervention. As highlighted by Heinemann et al. (2021), mutations introduced by genome editing or other genetic technologies are not reliant on the processes of evolution, but instead can be driven by human activity, to ensure such mutations establish and spread in the environment (Heinemann et al., 2021 https://doi.org/10.1525/elementa.2021.00086).

Thanks very much.

Hello fellow participants
I wish to make a small addition to Mrs Villafañe's useful list of potential impacts of Synbio ("it depends on the intended use, the risk evaluation results, and the ethical considerations on the application of a specific development") to suggest that unintended use is a serious aspect on the horizon. Unintended use may not be held to a risk evaluation or ethical and socioeconomic, cultural, considerations.

Two trends make unintended use a potential "business as usual" future. Both of these trends are an abandonment of containment as a risk mitigation and can fundamentally alter how genetic engineering applied to synthetic biology is done.

The first, as discussed elsewhere in this forum (eg here by Dr. Sirinathsinghji [#2636] and also in [#2637] of Topic 1: Question 2) is developments that allow the genetic engineering to be done outside of contained facilities. Not only is physical containment potentially becoming obsolete, the tools and kits for their use allow people with less or even no biosafety training (eg, see CRISPR in the Kitchen https://doi.org/10.1128/jmbe.00321-21, a paper about sending genome editing kits to students to use at home during lockdowns) or specialist knowledge of the biology of the exposed organisms to use them. Coupled with free access to databases, anyone anywhere can design their own nucleic acid 'guides'.

Outside of containment and the infrastructure needed to ensure that only the intended organism (or cell) is being exposed to the gene-altering reagents, there will be huge numbers of unintended organisms exposed. For the non-microbiologists in the room, there can be hundreds of millions of microorganisms on your clean skin and kitchen bench. For products intended for application to growing plants, there will be microorganisms, invertebrates, small animals, wild mammals and birds and potentially livestock, companion animals and perhaps people.

Up until now genetic engineering has been done in contained facilities for biosafety reasons, and because the techniques of transformation have been too inefficient to apply without the infrastructure to protect the intended cell or organism being modified. That way of doing genetic engineering allowed capture of all unintended exposures (for destruction) and the ability to assess the intended product before release from containment. Those two allowance would be lost in potential future ways of doing genetic engineering for synthetic biology. https://doi.org/10.3389/fgeed.2022.1064103

The second trend is the push to de-regulate some uses of genome editing and dsRNA (eg to cause RNA interference). An example is the "tiered" regulatory structures in which the risk of particular applications is predetermined and they are exempted from regulatory oversight. Unlike any other processes of gene-level technological intervention, including the use of chemical and radiation mutagenesis, genome editing and dsRNA would potentially have no oversight within these predetermined tiers. This is a brand new development and in my opinion a bona fide risk issue on its own.

With appreciation for your attention
Jack

Some biosafety concerns of SynBio application:
1. Ecosystem-level impacts
- Fitness advantages
- New class of pollutants
- Limits of detection for microbes
- Potential for rapid evolutionary change and mutations
- Removal of a population from an environment
2. Gene flow (e.g. Horizontal gene transfer)
3. Emergence of unpredictable properties (e.g. unexpected virulence of Mousepox, resistance in engineered gene drive experiments)

Also SynBio applications to replace natural materials (e.g. Valencene (Allylix), Nootkatone (Isobionics), Vanillin (Evolva), Squalene (Amyris), Artemisinin (Safoni), Shikimic acid (La Roche), Synthetic spider silk) may affect the third objective of the CBD if natural genetic resources are not needed anymore and no agreement on sharing the benefit of DSI.

O.A.El-Kawy

Dear colleagues,

I would like to thank you for the very interesting aspects that you brought to this part of the forum.

I think that the potential positive and negative impacts all need to be assessed on a case-by-case basis, depending on each individual organism, since even within a similar method, the application can be implemented differently depending on the tasks.

Regarding positive impacts of biosensing applications I would like to share this article https://www.frontiersin.org/articles/10.3389/fmicb.2020.618373/full.

In relation to the example of microalgae, which I brought to question 1a, there could be a number of positive impacts on the objectives of the Convention, such as those described for example in this review https://www.frontiersin.org/articles/10.3389/fpls.2020.00279/full.
At the same time, there is high level of uncertainty for microorganisms, including microscopic algae, especially in case of their unintentional or intentional release from photobioreactors or open-air research hatcheries into the soil, ponds, lakes, etc. Well, in the case of a large-scale release into the environment for organisms with a high potential for spread and reproduction, there are great difficulties in assessing the uncertainty, which may be caused by difficulties in prediction and evaluation of the rate of reproduction and distribution; in prediction and evaluation of the replacement rates of populations of wild relatives; in the evaluation of the ecological niche that LMO will occupy; in the evaluation of how replacement or modification of wild populations influence the ecological niche and influence the other organisms in it; in the monitoring of LM-aquatic organisms in natural habitats; in control of aquatic organisms in natural habitat; in the monitoring of aquatic organisms in aquatic (marine) areas beyond the national jurisdiction; in the neutralization of a particular species if the damage is revealed, and others (again, all in the case-by-case basis).

Uncertainty does not, of course, indicate a certain level of adverse impact, but it makes it very, very difficult to assess risks, accurately identify negative impacts for such organisms, or prove that there will be no negative impact. At the same time, most likely due to the high level of uncertainty, this may lead to a negative decision at the national level for such type of organism.

Best regards,
Galina

Hello,

My name is Lasse Middendorf, and I'm participating in this forum as a representative of the German Association for Synthetic Biology (GASB). I will comment on some claims raised by Mr. Then [#2608],  Dr. Sirinathsinghji [#2636], and Mr. Heinemann [#2639].

First, I want to agree with the other participants that the uncontrolled release of living-modified organisms (LMO) must be prevented, and risk-benefit assessments need to be conducted before any field testing of LMOs. However, risk assessments of LMOs cannot be based on the technologies that were used to create the organism. Instead, an organism's biological properties must be the primary attributes for the evaluation, regardless of their origin.
As a key component of synthetic biology is the standardization and modularization of genetic parts, the rational and precise modification of organisms with the means of synthetic biology results in tight control of their biological properties. The control over biological properties can thus be even better than for organisms created by conventional methods, such as breeding or random mutagenesis. Advances in artificial intelligence and the mathematical modeling of biological systems on all scales will likely further improve our ad hoc predictive capabilities (https://doi.org/10.1128/spectrum.01909-21 ; https://doi.org/10.1038/s41467-020-18008-4). Therefore, the higher complexity of the genetic modifications within the synthetic biology framework does not necessarily result in decreased predictability of their behavior, as suggested by other participants.

Further, it appears that other participants share the belief that control over LMOs is lost once they are released in the field. However, advances in incorporating non-canonical building blocks into LMOs can enable their locally- and timely-restricted release into environments (e.g., https://doi.org/10.1038/nature14121 ).

As Mr. Heinemann [#2639] correctly pointed out, modern tools, such as the CRISPR/Cas system, make the fundamental technologies of synthetic biology more accessible. The concern that using these tools outside traditional laboratories could lead to unintended modifications in other organisms is highly unlikely. The used systems, unless specifically designed, lack the regulatory genetic sequences for replication and modification of non-target organisms. Even if non-target organisms are eventually transformed with modern gene-editing tools, their high specificity diminishes the likelihood of an unintended genetic modification. The increased accessibility and low entry barrier to synthetic biology technologies can thus rather be seen as a chance for fair and equitable benefit sharing of these technologies and enable parties to build capacities in the research on and the development of these technologies.

Nevertheless, as modern tools for genetic engineering are comparably easy to use and highly efficient, adequate biosecurity frameworks need to be in place to prevent the uncontrolled release of LMOs. LMOs created with the means of synthetic biology do not pose an inherent threat because of the underlying technology, as stated in the document from Testbiotech that Mr. Then cited [#2608]. Such simplifications neglect the potential benefits synthetic biology can have on the three main objectives of the CBD. Carefully conducted risk-benefit assessments with a solid scientific foundation on the biological properties of LMOs thus need to be the preferred method in the regulatory processes of synthetic biology.

Interesting discussion so far! I am Onyeka Nwosu, a Senior Scientist with the National Biosafety Management Agency, Nigeria. Actively involved in risk assessments of modern biotechnology and in the development of regulatory guidances for modern and emerging biotechnologies.

Considering the increasing interest in the contained use activity(research) with technologies of SynBio around globe, I particularly think that in identifying potential positive and potential negative impacts vis-a-vis the 3 objectives of the convention, it should be guided by four major elements:
a. The precautionary principle.
b. The relevance of both the living and the non-living components of the process, history of use and the products of the synthetic biology.
c. The potential impacts of organisms, components, and products on the 3 objectives of the Convention
d. The consideration of direct and indirect effects also taking account of socio-economic and full life cycle analysis.

The above guide have re-echoed the importance of Synthetic Biology to majorly fall under the scope and obligations of Cartagena Protocol on Biosafety as well as under the scope of the Convention, especially with regards to socio-economic impacts.

Dear participants,

My name is Dr. Silke Fuchs and I am a Regulatory Scientist at Imperial College London with a background in molecular genetics.

I would like to add some comments on gene drives which relate to posts by Mr. Then [#2608],  Dr. Sirinathsinghji [#2636] and Prof. Dr. Ossama AbdelKawy [#2646].

Most of the core issues related to gene drives have been discussed under CBD since 2016 and I would also like to reiterate Prof. Dan Tompkins comment in topic 2 question 1 [#2614] that “Whilst it is not a suggestion in any way that any less rigour by applied to the consideration of applications with potential risks or benefits for biodiversity and conservation, it is recognizing that management goal considerations have already occurred (or are occurring) in other more relevant forums.”

In case of gene drive, since 2016, research on gene drive has progressed and discussions under CBD have evolved -  this is reflected by the ongoing work under Cartagena Protocol on Biosafety to develop guidance on additional aspects of risk assessment required for gene drive organisms, a direct response to the need expressed by Parties to have more support in preparation for possible reviews of future regulatory dossiers.
Since the last AHTEG met in 2019, there have not been major developments in gene drive research that would qualify gene drive as more imminent or that its intended use has changed (health, conservation primarily). Research is progressing on the same applications that were being considered in 2019, but it will take years for any gene drive technology to be considered for field evaluation (as noted by Dr. Owain Edwards for mice in a previous post [#2598]), and many more before any gene drive applications for health or conservation purposes is ready for use. No gene drive organism has been proposed for release yet.
Much of the work underway currently is seeking to improve and optimise existing constructs (not products) and to overcome challenges in developing gene drive systems that work in different target species. These developments are positive and represent scientific progress.
There is also a lot of work taking place looking at safety mechanisms (for example assessing molecular stability) and risk assessments. For gene-drive mosquitoes these include for example:
• James et al., 2023: Regulatory and policy considerations for the implementation of gene drive-modified mosquitoes to prevent malaria transmission - https://pubmed.ncbi.nlm.nih.gov/36920721/
• Connolly et al., 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 -https://pubmed.ncbi.nlm.nih.gov/33781254/
• EFSA 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 -https://www.efsa.europa.eu/en/efsajournal/pub/6297

In the future, any field testing of a proposed gene drive application should be part of a multi-phase research process, building on a large amount of prior work and decisions on whether to proceed should take into account socioeconomic considerations. Researchers and national authorities considering field releases of gene drive organisms can also draw on previous experience in agriculture, pest biocontrol, public health, and other fields, as well as guidance from authorities such as WHO, EFSA, NASEM and OGTR.

Best wishes
Silke

Dear colleagues,

This is Piet van der Meer. I am trained in biology and law, and I have been involved in the development, implementation, and review of biotechnology policies and regulations for over 35 years.

First my thanks to the Secretariat and to the moderator Dr. Cannell for kickstarting this online forum with some straightforward questions.

In response to the question “What could be potential positive and potential negative impacts vis-à-vis the three objectives of the Convention arising from such applications”: There are no general characteristics of synthetic biology that would make its applications inherently risky in relation to the objectives of the CBD. Whether specific applications  of synthetic biology may pose unacceptable risks to the objectives of the CBD will depend on the specifics of those applications and on the anticipated benefits.  In that context it is relevant to know that, as has been concluded on multiple occasions in discussions under the COP, organisms developed through synthetic biology will – at least in the foreseeable applications - fall under biosafety systems such as the Cartagena Protocol on Biosafety.

Likewise, the extent to which anticipated benefits of specific applications of synthetic biology for the objectives of the CBD can be effected, will depend on the specifics of those applications.

Yet, we can make a general observation with regard to potential benefits of synthetic biology: synthetic biology makes use of biological processes, which are circular by nature and which can be highly specific. The relevance of that specificity can be illustrated by the following. The production of products, e.g. detergents, from fossil fuels requires the application of chemical and physical processes to break down fossil fuels into smaller components and the subsequent application of chemical and physical processes to transform those components into final products. The production of products from renewables, can in many cases be done by the direct transformation from renewables - such as plant material - into final products through biological processes, without the high input of energy and chemicals that required for chemical and physical processes. As other colleagues in this and other threads have recognized, synthetic biology - through its 'design' characteristic - can increase the efficacy and efficiency of those biological processes.

My name is Markus Schmidt, I am the founder of Biofaction (Austria) and was invited by the Global Youth Online Union to participate in the online forum.

Synthetic biology may enable the sustainable use of natural beneficial compounds (aim 2 of the CBD) that previously could either a) only be produced through energetically inefficient forms of synthetic chemistry or via agriculture with negative effects on wildlife or b) not be produced with synthetic chemistry or harvested from nature at all.
Through synthetic biology there are more and more examples where an efficient production of molecules of interest (e.g. flavonoids, terpenoids and other secondary plant metabolites, but also pheromones for an environmentally friendly way to protect crops from pests) is enabled by breaking down their complex biosynthetic pathway into standardized components which can be transferred to engineered microorganisms to promote their production in bioindustry.
Since many of the compounds of interest only occur in plants in very tiny amounts, synthetic biology is able to produce these compounds in larger quantities in a much more efficient way (compared to growing the plants themselves and extracting these tiny amounts). For those compounds that could so far no be produced in any economically feasible form, synthetic biology makes it now possible to produce these molecules of interest so several tests can be carried out to see if these compounds have interesting pharmaceutical, antimicrobial or other uses.

See for example:
https://synbio4flav.eu/
https://www.isobionics.com
https://biophero.com/

In principle, this could also contribute to aim 1 of the CBD, the conservation of biological diversity, as alternative and more cost effective ways of production should ease the pressure of harvesting wild plants, reduce demand for agriculture land and avoid land use change from natural habitats to agricultural use.

To support this potential positive effect it is necessary to characterize well the wild species and provide the information in an accessible, and increasingly digital form. There are several collections and repositories, such as MIRRI https://www.mirri.org/microbial-resources-data/ that aim to make this data available, so that it can be accessed and used in an efficent and smart way. This data driven approach could spark the next wave in bioindustry, something that has been called bioindustry 4.0 in analogy to the forth industrial revolution.

Greetings, my name is Nicole Buan and I am an Associate Professor of Biochemistry at the University of Nebraska-Lincoln in the United States. I am also a member of the Engineering Biology Research Consortium (EBRC), where I contributed to the recent Climate and Sustainability roadmapping (https://ebrc.org/focus-areas/roadmapping/). Thank you to the Secretariat and Dr. Cannell for their work to promote discourse on this important topic, and to all the contributors for their thoughtful contributions and valuable perspectives.

To add to the points raised by other participants of this forum, I would like to offer the following considerations with respect to the potential impacts of synthetic biology which can be used to guide assessment strategies.

1) An outcome of synthetic biology is to increase biodiversity, by accelerating trait shuffling between organism lineages that would not otherwise breed successfully, and to facilitate cross-domain genetic transfer. At a certain level of breeding or genetic engineering, an organism would qualify for new species designation. Thus, the issue may not be with “synthetic biology” but with widespread deployment of known biological toxins, which is one small aspect of what can be achieved through synthetic biology. The Convention may consider a nuanced classification scheme that takes the effects of a modification into primary consideration so as not to disincentivize development of new technologies that do not bear the same risks.

2) Generating LMOs is time-consuming and expensive. As a result, commercial considerations in large part drive investment in research and development. However, without significant financial backing, the impacts of any synthetic biology are unlikely to be realized due to lack of funding for scale-up and field application. Thus, robust risk assessment is most critical for technologies as they approach commercial deployment. In the United States, synthetic biology research and generation of LMOs is heavily regulated and annually assessed at research-intensive universities, institutes, and in industry (for example, see https://www.aphis.usda.gov/brs/fedregister/coordinated_framework.pdf). For deployment, regulatory tasks are housed with the US Environmental Protection Agency or the US Food and Drug Administration. Jurisdictions may consider the balance of economic drivers and regulatory compliance structures to build confidence in emerging synthetic biology technologies, which will vary between regions.

3) Consider that synthetic biology tools and approaches build on what is already present in nature. Extant organism lineages have evolved over 3+ billion years, and natural organisms far exceed what humans can design with biological materials. Synthetic organisms would have to compete in the same environments with highly evolved natural organisms for the same resources. LMOs are subject to the same evolutionary pressures all organisms face. Part of the risk assessment should consider the trait “half-life”: ability to reproduce in the field, generation time, fitness benefit and rate of adaptation/selection for resistance (see https://www.nature.com/articles/nbt.3974 for some issues to consider).

4) While large-scale deployment of GMOs and LMOs may affect the local ecosystem, all large-scale industry, including agriculture, affects the ecosystem and ultimately the global climate. Regulations may consider whether large-scale deployment of a non-GMO/LMO is expected to have similar ecosystem effects as deploying an LMO. For example, what are the expected impacts between deciding to clear-cut a forested area to plant agronomic crops or expand livestock grazing vs replacing a corn variety with an LMO corn in an existing field?  Should routine ecosystem surveillance be implemented (ecological impact studies) to regularly assess environmental and biodiversity impact? Which industries should be subject to such regulation? Should these types of studies and regulation inform trade agreements?

5) The potential positives of using synthetic biology to withstand and respond to pending climate changes can be considered to outweigh  potential negatives. The US Biden administration has recently signed Executive Orders and Bold Goals to promote growing the sustainable bioeconomy, which includes promoting synthetic biology and biomanufacturing objectives in every industry:
a. https://www.whitehouse.gov/briefing-room/presidential-actions/2022/09/12/executive-order-on-advancing-biotechnology-and-biomanufacturing-innovation-for-a-sustainable-safe-and-secure-american-bioeconomy/
b. https://www.whitehouse.gov/wp-content/uploads/2023/03/Bold-Goals-for-U.S.-Biotechnology-and-Biomanufacturing-Harnessing-Research-and-Development-To-Further-Societal-Goals-FINAL.pdf

Dear colleagues,
My name is Stephanie James. I am a microbiologist with over 40 years of experience involving research on infectious diseases, currently employed by the Foundation for the National Institutes of Health.

I am pleased to see several recent posts that are recognizing the promise of biotechnology applications to address some of the world’s most serious and ongoing problems. For example, gene drive mosquitoes, mentioned by several participants, are being investigated in response to a need expressed by the World Health Organization (WHO) for development of new tools to combat malaria and other vector-borne diseases, which cause more than 700,000 deaths annually (https://apps.who.int/iris/bitstream/handle/10665/336031/9789240013155-eng.pdf). The WHO states that progress against malaria has stalled in recent years, and incidence is again increasing in several countries (https://www.who.int/publications/i/item/9789240064898). The healthcare reality is that the level of funding required for malaria control consistently lags by billions of US dollars behind the amount required to achieve global goals (https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(19)30165-3/fulltext; https://www.who.int/publications/i/item/9789240064898). Therefore, both WHO and the African Union Assembly have taken the position that new technologies such as genetically- and gene drive-modified mosquitoes should be investigated for their potential contribution to the continued fight against malaria and other vector-borne diseases of public health concern (https://apps.who.int/iris/bitstream/handle/10665/336031/9789240013155-eng.pdf; https://au.int/sites/default/files/decisions/37294-assembly_au_dec_642_-_664_xxix_e_1.pdf ).

The potential benefit of gene drive technologies must, of course, be considered in the context of possible risks, which have been raised by participants in this forum. Developers are aware of these risks, and as mentioned by Dr. Silke Fuchs [#2666] there is much work on risk assessment and safety mechanisms ongoing. Requirements for risk assessment and regulation of gene drive mosquitoes are currently being considered under the Cartagena Protocol on Biosafety, as well as by a range of other expert groups. These include those cited by Dr. Fuchs as well as:
• The World Health Organization – Guidance framework for testing of genetically modified mosquitoes, second edition https://www.who.int/publications/i/item/9789240025233
• James et al., 2020 – Toward the definition of efficacy and safety criteria for advancing gene drive-modified mosquitoes to field testing  https://www.liebertpub.com/doi/full/10.1089/vbz.2019.2606
• African Union Development Agency - NEPAD – Strengthening AU member states’ regulatory capacities for responsible research towards elimination of malaria in Africa. https://www.nepad.org/publication/position-paper-strengthening-au-member-states-regulatory-capacities-responsible

Hello, Dr Brinda Dass from the Foundation for the National Institutes of Health in Maryland, USA. I am a molecular biologist by training and served on the 2019 AHTEG on RA/RM. Thank you to Dr Martin Cannell for moderating the discussions and the Secretariat for the opportunity to comment.
The scientific method is an iterative one with most efforts aimed at refining and selecting the most optimal design combinations as can be seen in design-build-test approaches commonly used (See Topic 1a: Dr Mozgova [#2602] re: sophistication of methods and design-build-test). Synthetic biology products are not different in this regard including engineered gene drive organisms. Discovery science is a cost and resource intensive process but one focused on delivering a safe and effective product. Beyond the intent of developers and the investigational products they eventually choose to present for approval by authorities there is also a system of regulatory checks and balances. All regulatory systems operate under defined protection goals such as safety to human and animal health and safeguarding the environment and biodiversity. As such a regulated LMO product cannot make it to market without a pre-market risk assessment being performed (See Topic 1a: Mr Then [#2607], re: need regulatory systems that provide sufficient oversight). In the case of Parties to Cartagena Protocol this is an essential and necessary step. Conducting a science-based risk assessment is a pro as it will ensure that environmental safety is taken into consideration as well as allow public participation to ensure that communities have a say in which products could be tested and possibly brought to market. Further, the problem formulation step of risk assessment allows an exhaustive query of all potential pathways to possible harm (https://pubmed.ncbi.nlm.nih.gov/33781254/ ) and seeks input from a wide range of stakeholders including local communities and IPLCs. This process aids developers and decision makers in determining the types of data and information that are most informative as well as discriminating pathways that are most likely to lead to result in a described harm. Synthetic product developers may take other approaches including safe by design (DOI: 10.3390/ijerph18041554; 10.1007/s11569-017-0301-x) as an early risk mitigation method.
Also, not all products and use cases will have the same risk profile. Risk should be assessed on a case-by-case basis determined by the nature of the product but also its intended use and area/location of use (1b Dr Agbagala [#2595]; Dr Galina [#2660]). Several products that have been mentioned such as biofuels or biosynthetic products such as flavors (1a Dr Safendrri {#2629]; https://www.ginkgobioworks.com/offerings/nutrition-wellness/ ) could be produced in bulk but in fully contained systems with a risk profile that is much different than a product that is intended to be used in the environment or at a population level. It is plausible that some products that are synthesized in full containment and used with appropriate risk mitigation features built in could appear on the market in a shorter time frame (5 years or less). Others such as engineered gene drive mosquitoes may have a longer time frame for development and testing (5-10 year or longer) as has been mentioned.
The risk assessment process allows ensures taking into account the cost of not taking any action.
With specific regard to advancing synthetic biology research and development a necessary pro would be to have the requisite capacity and legal remit in-country to conduct risk assessments and scientific review of regulatory applications (1a Mr Taskin [#2642], Prof Tomkins [#2648]). Though many countries may not be directly involved in discovery science related to synthetic biology they should still be supported in scientific and regulatory capacity building and maintenance to ensure equitable sharing of any benefits from these technologies and products (Topic 1b Dr Mekonnen [#2581]; Mr Ngezahayo [#2618]). Further, efforts should be made to allow transfer of technological knowledge so that in-country research can occur to support national needs and use local and national resources. Data sharing and data portability are important considerations from a perspective of access and benefit sharing. Lack of technical and regulatory capacity will otherwise be a detriment to bringing any synthetic biology products to market and keep those nations from making informed decisions that could be valuable to their peoples.
Most academic and industrial scientists are intentional in their research and want to be in compliance with required laws and regulations. Most products that are marketed will be aiming to comply with testing, labeling, reporting, marketing etc. requirements as applicable (1a Ms Beeckman [#2683], Prof. Alphey [#2690]). This is a pro that should be recognized for the biotechnology and synbio fields at large as well as the role of CBD and Cartagena Protocol.
Thank you.

Dear participants,

My name is Luciana Ambrozevicius, I work for the Ministry of Agriculture and Livestock in Brazil. 

There are three important areas that I understand can have a huge contribution from synthetic biology, related with biodiversity conservation and sustainable use (already mentioned in the AHTEG report UNEP/CBD/SYNBIO/AHTEG/2015/1/3):

- “In the area of bioenergy applications that rely on synthetic biology, some models indicate a potential reduction in greenhouse gas emissions, which would contribute to mitigation of climate change and thereby to the sustainable use of biological diversity” (https://pubmed.ncbi.nlm.nih.gov/34739924/; https://www.sciencedirect.com/science/article/pii/S1369527421001466);

- “Agricultural and agroforestry applications of synthetic biology, such as abiotic stress tolerance or micro-organisms modified for increased nitrogen fixation, may lead to restoring  productivity of depleted agricultural land and to increased crop productivity on existing agricultural land” (https://reader.elsevier.com/reader/sd/pii/S2773237122000065?token=7751D7CE38E0C426FC6FF3C104595C2A2B23310AC6F03005D433A93E70ACC6E606B07267A1916C110E08FC9D7B3A9E27&originRegion=us-east-1&originCreation=20230323173151);

- “Medical and nutritional applications may lead to healthier populations, which is a pre-requisite for the conservation of biological diversity” ((https://www.mdpi.com/1420-3049/27/20/6933); https://pubs.acs.org/doi/10.1021/acssynbio.1c00576): 

It’s also important to emphasize as part of the assessment at the horizon scanning process that benefits of the technologies should be considered. Recently we approved the Target 17 under the Kunming-Montreal GBF: “Establish, strengthen capacity for, and implement in all countries in biosafety measures as set out in Article 8(g) of the Convention on Biological Diversity and measures for the handling of biotechnology and distribution of its benefits as set out in Article 19 of the Convention” and the horizon scanning process is an important tool to identify those benefits specially to promote developing countries participation in the R&D. 

I also agree with #2673 regarding the fact that “there are no general characteristics of synthetic biology that would make its applications inherently risky in relation to the objectives of the CBD”.

Thanks,
Luciana

Dear participants,
I appreciate your wonderful comments.

I am Dr. Bong Hyun Sung, a member of the Synthetic Biology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), and working as the Program Manager for Synthetic Biology at the Korea National Research Foundation (NRF).

As noted by several previously, we agree that potential positive and negative impacts should be evaluated on a case-by-case.
The positive side seems to be something we can consider if only the results come out as we intended. Because we haven't understood everything about life yet, I think the biggest negative impact is to have unintended results.

Greetings,

I’m Dr. Becky Mackelprang, and I am the Associate Director for Security Programs at the Engineering Biology Research Consortium (I provide further introduction in #2691).

In response to question 1a, I identified ways in which synthetic biology may be used to mitigate environmental pollution, sequester greenhouse gases, and aid in the conservation of biodiversity [#2691]. The positive impacts of these and other uses (e.g., see “Environmental Biotechnology” in Engineering Biology: A Research Roadmap for the Next-Generation Bioeconomy; https://roadmap.ebrc.org/2019-roadmap/sectors/environmental-biotechnology/ and Engineering Biology for Climate & Sustainability: A Research Roadmap for a Cleaner Future; https://roadmap.ebrc.org/engineering-biology-for-climate-sustainability/) could be significant in meeting the objectives of the Convention.

Negative impacts of synthetic biology are, of course, possible. However, the use of synthetic biology does not make something inherently risky (see Mr. Piet van der Meer, #2673; Mr. Lasse Middendorf, #2661; Dr. Nicole Buan, #2678). As noted by Dr. Brinda Dass [#2692], “risk should be assessed on a case-by-case basis determined by the nature of the product but also its intended use and area/location of use” (see also Ms. Maria Lorelie U. Agbagala, #2595; Dr. Galina Mozgova, #2660; Dr. Bong Hyun Sung, #2705). Where regulatory programs are not mature, as may be the case in countries without active synthetic biology research programs, they should be supported to ensure equitable access to any ensuing benefits (see Dr. Brinda Dass; #2692).

Regulatory processes should balance risk with potential benefits. Some degree of risk may be deemed acceptable when negative outcomes of inaction are assured and lower-risk approaches are not feasible on relevant timescales. “Safety by design” (e.g., genetic safeguards and firewalls) approaches could be employed in some cases to minimize the likelihood of potential negative impacts (see Pei et al., 2022; https://doi.org/10.1038/s41467-022-29889-y).

Hi everyone, my name is Dr Francis Djankpa. I come from Ghana. In Ghana, we are not yet into synthetic biology. We are dealing with regulating GMO and NGT products. I have been reading insightful and learned contributions from members. I believe this forum is an opportunity for us to start a similar dialogue in Ghana in order get started. Thank you all

Hello everyone, I am Amelie Wamba from Cameroon and just like what Dr Francis said for Ghana, Cameroon is yet to open the discussions around these topics. Being here is a huge learning experience which I hope would be of use when the time comes for Cameroon to start working on synthetic biology. Very enriching inputs here and thank you for the links for further research on the topic.

Best regards,

Dear all,

since this online discussion is about potential positive and negative impacts the new report of Testbiotech might be of interest to you which elaborates on technology assessment and sustainability aspects of Synbio plants (also called plants derived from new genomic techniques, NGTs). We come to the conclusion that the existing approval procedures should be updated and supplemented by a comprehensive technology assessment (TA). The aim of a TA would be a full and comprehensive investigation of the potential advantages and disadvantages of potential applications, including the ecological and socio-economic impacts. Besides allowing excessive expectations to be critically reviewed, it would help to prevent potentially negative impacts on ecosystems, safeguard the natural balance and limit, as far as possible, environmental interventions. The concepts of nature conservation and environmental protection are largely based on the principle of avoiding interventions that could damage natural self-organisation capacities in protected areas or that could compromise sustainability criteria relevant for land use. These concepts also have to be applied in the field of Synbio. From this perspective, the introduction of a technology assessment into LMO and Synbio regulation can help to effectively control and limit the type and number of potential releases of genetically engineered organisms.

Appropriate criteria would be needed to make fact-based decisions on sustainability and any potential benefits of Synbio for example in agriculture or nature protection. These would enable a technology assessment to identify negative effects at an early stage in breeding, agriculture and food production and, above all, prevent alleged Synbio ‘solutions’ from creating new problems for the environment, ecosystems and future generations.

See the full report: https://www.testbiotech.org/en/content/genetic-engineering-agriculture-between-high-flying-expectations-and-complex-risks

Products to decrease pesticide and land use in agriculture;  to reduce chemical and plastic pollution for instance enzymes capable to degrade toxic compounds or PET bottles or expand biodegradable alternatives to plastics, alternative to threatened horseshoe whose  blood is  used to test for contamination in biomedic applications, etc

Dear colleagues,

As many others here I share the concern that the impacts of particular technologies or applications are highly dependent on factors like intended (#2635) or unintended (#2639) use of these technologies, intended and unintended receiving environment, cumulative, interactive and scale effects, reliability of the technology as well as accuracy of the underlying understanding.

I concur with others that the trend to modify both the wild and in the wild are giving rise to highly unpredictable scenarios and thus largely increasing risks and the quality and quantity of potential negative impacts. The trend to use gene drives as a form of pesticide (e.g. 21 out of the 32 proposed and current insect targets for gene drive development are intended for agricultural pests, Wells & Steinbrecher 2022, attached to my post under Question 1a) holds substantial risks for serious direct and indirect negative effects. It would likely not enhance resilience but compromise resilience or result in the failure to do the actions that would strengthen resilience due to ecological interactions and networks and that may only thrive if supported by a systems approach. Here, again, aspects mentioned above, like unintended use, will likely enhance risks and unpredictabilities.

It is likely not possible to assesses and to sufficiently and reliably predict the outcomes of strong interference in natural systems, especially as most of these systems are still poorly understood. In this context I would like to mention two areas of evolving knowledge and active research that deem helpful in this context of attempting to predict impacts. Both show the importance of checking assumptions of (current) knowledge and to recognise the lack of knowledge or the need to replace old knowledge with new questions and understanding.

1) A field of science that is still very much at its beginning is that of the forest communication and support system, that largely takes place underground and has thus escaped the observation -and imagination- of forest science. As it stands, different species of fungi along with the root systems of the plants combine to be an intricate and vast network of mycorrhiza now often referred to as the “wood-wide web” (e.g. Beiler et al. 2010). In has been found to be not only a network that exchanges or transports nutrients, but also distributes and channels information, e.g. information related to stressors or disease and is reported to have capacity for memory (Simard 2018). What would be the effects of using dsRNA sprays in forestry, releasing modified trees, or insects or microorganisms, and how to predict this without sufficient knowledge in place?
Beiler KJ, Durall DM, Simard SW, Maxwell SA and Kretzer AM. (2010). Architecture of the wood-wide web: Rhizopogon spp. genets link multiple Douglas-fir cohorts. New Phytologist 185:543-553. https://doi.org/10.1111/j.1469-8137.2009.03069.x  
Simard SW. (2018). Mycorrhizal Networks Facilitate Tree Communication, Learning, and Memory. In Baluska F, Gagliano M, Witzany G (eds). Memory and Learning in Plants. Signaling and Communication in Plants. Springer: Cham. doi: https://doi.org/10.1007/978-3-319-75596-0_10 

2) Releasing synthetic biology technologies or organisms into the wild and/or to modify the wild is highly related to the field of invasion science (“the systematic investigation of the causes and consequences of biological invasion”). Those active in the field have recently stated that there is the need for greater predictive power for predicting ecological impacts of invasions under rapid environmental change. The abstract of a recent publication begins as follows:
“Abstract: Unprecedented rates of introduction and spread of non-native species pose burgeoning challenges to biodiversity, natural resource management, regional economies, and human health. Current biosecurity efforts are failing to keep pace with globalization, revealing critical gaps in our understanding and response to invasions. Here, we identify four priority areas to advance invasion science in the face of rapid global environmental change. First, invasion science should strive to develop a more comprehensive framework for predicting how the behavior, abundance, and interspecific interactions of non-native species vary in relation to conditions in receiving environments and how these factors govern the ecological impacts of invasion. A second priority is to understand the potential synergistic effects of multiple co-occurring stressors— particularly involving climate change—on the establishment and impact of non-native species. Climate adaptation and mitigation strategies will need to consider the possible consequences of promoting non-native species, and appropriate management responses to non-native species will need to be developed. The third priority is to address the taxonomic impediment. The ability to detect and evaluate invasion risks is compromised by a growing deficit in taxonomic expertise, which cannot be adequately compensated by new molecular technologies alone. Management of biosecurity risks will become increasingly challenging unless academia, industry, and governments train and employ new personnel in taxonomy and systematics. ….” Ricciardi et al. 2021.
https://cdnsciencepub.com/doi/10.1139/er-2020-0088


The trend of dual use – brought up in various threads - will need to be taken on board and assessed for or alongside each of the technologies, applications and trends.

Finally, I would like to briefly address the issue of “naturalness” and the trend to declare that either the outcome of synbio applications or the action of synbio techniques are what can be found in nature. This is often taken to imply that, as a consequence, the product or action is intrinsically safe and either should not be regulated (debate on genome editing) or should not be regarded as “new” or artificial or particularly problematic. This trend is also related to the “null-segregant strategies” discussed in the parallel thread of question 2.  It will be important to actively pay attention to this ‘as nature’ trend, as it has the capacity to colour perceptions. This is for example also related to the definition and perception of gene drives, e.g. whether naturally occurring ‘selfish genetic elements’ such as transposons should or could be called ‘natural gene drives’. Our group has found such a redefining of gene drives highly problematic for various reasons. For those interested: Wells MA, Steinbrecher RA. (2022). Natural selfish genetic elements should not be defined as gene drives. Proc Natl Acad Sci U S A. 119(34):e2201142119. https://doi.org/10.1073/pnas.2201142119

With kind regards,
Ricarda

Greetings all,

I would like to thank the moderator and participants for what has been a very enriching conversation that has raised vital points through which I am learning a lot.

I would just like to finally address the issue of claimed benefits, and the need for monitoring of synbio products, not only during the research phase, but also post approval.  It is vital that information is shared to facilitate understanding of how products are performing post commercialisation, rather than relying on anticipation of potential benefits of those in development.  Problems such as a lack of cost-effectiveness as well as unintended environmental persistence during trials, and failure to meet early claims regarding the potential to eliminate local mosquito populations, for example in the case of LM mosquitoes need to be shared so as to inform on future, related product development and potential releases. This may facilitate prioritisation of public health (for health applications) programs to balance cost-effectiveness and use of other existing alternatives, such as increased access to diagnostics and treatments, or investment in social determinants such as improved housing conditions amongst other crucial factors e.g. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-023-04499-1, or other potential innovations.


Likewise, numerous genome edited crops have been approved but commercialisation is lacking despite some editing techniques being around for decades. It appears only one genome edited crop is currently cultivated commercially (CIBUS soybean), with reports of low adoption rates, yet there is little information to inform on the reasoning for lack of adoption or potential failures, or what in general the current adoption rates for these new technologies are. This lack of information hinders analysis of those products themselves, as well as emerging products in development.

Any support of synthetic biology research,  e.g. from the WHO for LM mosquitoes research, needs to be  contextualised by the actual outcomes measured against the claimed benefits.

Thanks very much
Eva

I am Dr. Trine Antonsen, I introduced myself in an earlier post. I appreciate Dr. Ricarda Steinbrecher’s comments about naturalness (#2730). The term’s meaning is highly debated, inaccurate and varies across cultures. For those interested, we targeted this aspect in a recent research project and published this paper: DOI: 10.5840/enviroethics202143020 

Abstract: New techniques for modifying the genomes of agricultural organisms create difficult ethical challenges. We provide a novel framework to replace worn-out ethical lenses relying on ‘naturalness’ and ‘crossing species lines.’ Thinking of agricultural intervention as a ‘negotiation’ of ‘integrity’ and ‘agency’ provides a flexible framework for considering techniques such as genome editing with CRISPR/Cas systems. We lay out the framework by highlighting some existing uses of integrity in environmental ethics. We also provide an example of our lens at work by looking at the creation of ‘cisgenic’ (as opposed to ‘transgenic’) potatoes to resist late potato blight. We conclude by highlighting three distinct advantages offered by the integrity framework. These include a more fitting way to look at the practice of scientific researchers, a more inclusive way to consider ethics around agriculture, and a more flexible way to provide the ethical grounds for regulation in different cultural contexts. 

Another useful source is Helena Siipi’s conceptual analysis Dimensions of naturalness: DOI: 10.2979/ete.2008.13.1.71

----Posted on behalf of Antonio Costa de Oliveira, Brazil----

Hello, This is Antonio Costa de Oliveira, from Brazil. I've been trained in Agriculture and Molecular Biology. One of the main points that Synthetic biology  can contribute to the current environment is through the biodegradation of molecules released by the technological advances of production systems. As Mr. Piet van der Meer well pointed out, these organisms can speed and maximize the efficiency of degradation processes, and help us to reshape the planet. The very same threat that plastics and other compounds cause in yet conserved biological ecosystems can be mitigated by new organisms designed by synthetic biology.

Hello everyone.  My name is Adam Cornish and I work in the Office of Agricultural Policy at the U.S. Department of State.  I am pleased to see the continued discussion on the forum and thank the moderators for their work and the thoughtful comments of the other participants in the forum.

Research in the field of genetic engineering, much of which is conducted by public-sector institutions and U.S. companies (private sector), improves our understanding of biological systems and advances innovation to address food security, protect natural resources, discover novel energy sources and medicines, and respond to the negative impacts of climate change.  Many of these applications can contribute to the conservation and sustainable use of biological diversity.  Indeed, over forty years of research, education, product development using recombinant DNA techniques has led to clear benefits relevant to the Convention’s objectives, and these benefits will continue to emerge with continued application of biological engineering tools and techniques.  There is a broad range of applications for synthetic biology technologies with potential benefits for biodiversity, including applications that assist in species conservation efforts, environmental remediation, and invasive species control.  Genetic engineering has already improved crop production methods by reducing soil erosion, decreasing fuel and chemical pesticide use, increasing disease- and pest-resistance within plants, increasing on-farm insect biodiversity, enhancing crop product quality, and improving farm productivity and farmer income.  Put simply, genetic engineering has helped agriculture do more with less and reduced agricultures’ impact on biodiversity and the environment.

The United States believes that regulation and oversight of technologies, like some synthetic biology techniques, should protect safety, health, and the environment while avoiding unjustifiable barriers to innovation, stigmatization of new technologies, or creation of trade barriers.  Regulation and oversight should be based on the best available scientific evidence and be implemented with an awareness of the potential benefits and the potential costs of such regulation and oversight.  To the extent possible, new technologies and their applications should be considered within existing governance and legal frameworks.  As with all technologies, policies should enable innovation and investment, and avoid ex ante regulation.  A balanced approach should be taken to provide sufficient flexibility to continually accommodate new knowledge, taking into account the evolving nature of emerging biotechnologies and their applications.

It is a priority of the United States to support and expand the use of biotechnology and biomanufacturing to encourage a robust bioeconomy.  We see biotechnology and biomanufacturing, including synthetic biology, as critical tools to achieve societal goals. Through Executive Order 14081 “Advancing Biotechnology and Biomanufacturing Innovation for a Sustainable, Safe, and Secure American Bioeconomy,” the United States will coordinate a whole-of-government approach to advance biotechnology and biomanufacturing towards innovative solutions in health, climate change, energy, food security, agriculture, supply chain resilience, and national and economic security.  The policy relies on principles of equity, ethics, safety, and security that enable access to technologies, processes, and products in a manner that benefit the global community.  Among other aspects of this policy, the Biden-Harris Administration emphasizes the importance of international engagement, including with emerging economies, international organizations, and non-governmental organizations to promote and protect the United States and global bioeconomies.

The U.S. government welcomes the opportunity to work with partners to better understand the state of scientific advances, to consider appropriate steps to mitigate the potential risks from applications of synthetic biology, and to engage with stakeholders to achieve benefits.

I am Felicien AMAKPE (PhD) the focal point in charge of biosafety in the republic of Benin. Thank you all for the quality of the information shared in this forum. I am learning a lot on the different strategies that will help us take the best advantages from the safe application of the synthetic biology.
There is no doubt, future development and application of Synthetic biology have the potential of improved technologic achievement which will bring great progress in Africa and the entire developing world.
As pointed out by some colleagues, the fair and equitable sharing of benefits from the access and utilisation of genetic resources will become more and more challenging with the new development of synthetic biology. Horizon scanning will then focus on this aspect that are part of the implementation of the GBF.
Most biotechnology development are being rapidly adopted in Africa on crops and for sure, it will be the same trend for the synbio development related to agriculture and pest control in most developing countries. More attention should be given to the impacts on developing countries and the IPLCs on their capacity, maladaptive innovation and resilience to make sure that decisions are not only based on the daily need or challenges, but on real lasting deep understanding of the entire aspects and facets of advantages/benefit and cost of the technologies. Further investments in the human capitals of the developing countries are then required.
When it will come the future application of synthetic biology in the agricultural areas, we should really take into account of the pollinators and in particular the honeybees which will be directly or indirectly impacted by the synthetic biology development in the world with the same acuity as most classic GM technologies in this sector. Horizon scanning will then particularly target on Pollinators and the bees in both developed and developing countries as the whole world is facing dramatic decline in bees and pollinators. But the situation in the developing countries is almost unknown as the bees in these areas are still believed to be aggressive and resistant to biotic and non-abiotic factors.
Other areas will be the impact on snakes, and other envenoming animals (reptiles, mice, insects and other Arthropoda) in the tropical areas. First, the potential prey-predicator unbalance that will potentially work out from the application of synthetic biology and related technologies in the process of anthropization of the global environment will surely lead to more envenoming from such animals due to increased contact with them or increased aggressivity. Second, what will the impact of the application of the synthetic biology on the toxicity of the venom from these animals? Unfortunately, envenoming is a neglected disease which mainly occurs in poor rural and disadvantaged areas. Such social categories deserve particular care when prioritizing the different actors to be involved in horizon scanning in the future application of synthetic biology.

This is Tobias Erb, biologist and chemist by training, scientific member of the Max Planck Society, Director at the Max Planck Institute for Terrestrial Microbiology, and expert member of the 5th Gene Technology Report of the Berlin-Brandenburg Academy of Sciences and Humanities in Germany, nominated by the German Government for this panel.

I appreciate the many contributions, views and comments that have been shared in this forum and would like to thank the moderators for managing our discussions.

Before commenting on the individual risks and benefits, I would need to express my concern about some of the statements raised in this forum, which I feel are not very much supported by scientific arguments.

As examples: I disagree that genetic modified organisms have not been released to the environment, thus far, e.g. as raised by [#2639]. In fact every modern crop species selected by human activities (e.g., created through classical and chemical induced breeding technologies) is a genetically modified organism that is “released” to the environment.

I also disagree that genome editing should be considered different from classical breeding technologies. In fact, this technology is actually much more controlled and accurate than current practices, as the off-target rate is much lower compared to other breeding practices and actually even lower compared to natural mutation rates. 

Thus, I would appreciate to put discussions onto a more solid scientific ground and identify areas, where science can contribute to answer open questions. There is a large body of literature on biosafety that was already mentioned in previous posts and the scientific community continues to collect and evaluate risks associated with genetically modified organisms.  

I agree that products should be evaluated in terms of their safety and their potential impacts, but not restricted per se under an undefined “synthetic biology” umbrella label, as already discussed e.g. by  [#2661]. Thus, as for any other product, a risk assessment and a fair evaluation of risks and benefits, as well as past experiences needs to be performed.

As to the potential benefits:

Synthetic biology products carry the potential to directly address many goals of the UN sustainable development goals, in particular #2 Zero Hunger (improved crop productivity, robust crops and food security), #3 Good Health (development of new antibiotics, nutrient-enriched food), #6 Clean Water (new biosensors and microorganism-based waste water treatment), #7 Affordable & Clean Energy (methanol/formate based bioeconomy, biogas production), #11  Sustainable Cities (advanced waste stream management, biological energy sources), #12 Responsible Production (carbon cycle management, biodegradables, non-fossil sources), #13 Climate Action (carbon capture and utilization technologies), as well #14 & 15 Life on Land and in Water (conservation of biodiversity due to improved land use).

Indirectly, synthetic biology can also contribute to UN SDG #1 No Poverty & #8 Economic Growth (providing better and cheaper products for everyday life and providing opportunities to develop a global bioeconomy market in which the different regions will profit from each other), as well as #4 Quality Education (by providing new knowledge about biological and planetary systems).

Dear colleague,
Many thanks to Martin Cannell to moderate this rich discussion. My name is Margret Engelhard and I am working at the German Federal Agency for Nature Conservation in the area of GMO Regulation and Biosafety. Also I was member of the previous Synthetic Biology AHTEGs.

Synthetic Biology is a powerful tool to reshape organisms and that is the main reason, why there are hopes connected to its applications, which is also reflected on the post by the colleagues that emphasize the potential positive impacts. New characteristics do always have impacts that need to be assessed, both on a case by case basis but also on more general terms, when LMOs have common characteristics.

One recurring focus within the topic of potential negative impacts have been gene drive organisms. I appreciate that there is awareness among researches and ongoing work on safety mechanisms and risk assessment, as pointed out by Silke Fuchs [#2666] and Stephanie James [#2679]. Our own work in the area has, however, shown that we face a number of challenges to evaluate genetic engineering in wild populations due to the complexity of the receiving ecosystems. The confinement of gene drive applications in time and space is unclear but will be influenced by the design of the drive, the biological characteristics, the biology of the organisms and, importantly, interactions with the environment (other species and functional processes).

In the last years we have worked on methods to evaluate the potential for unintended negative effects on ecosystems and biodiversity. Modelling has been proposed as a potential solution to assist the risk assessment. However, despite of many models being developed for gene drives, virtually none of the models to date focus on potential effects on biodiversity and ecosystems (Frieß et al. 2023, doi: 10.1016/j.ecolmodel.2023.110285 ). Also, most models lack biological realism which is paramount to predict gene drive spread and persistence (Verma et al. 2023, doi: 10.1086/722157). Developing and validating models to assist the assessment of biodiversity effects from gene drives or any other form of synthetic biology released into the environment will be a major challenge for the next 10-20. Because gene drives, although meant for environmental release, are difficult to test in the field (Simon et al. 2018; doi: 10.15252/embr.201845760) predictions from validated fit-for-purpose models should be available to assist the risk assessment prior to any environmental release of a gene drive into the environment. The same holds for a binding long-term monitoring.

With regard to potential positive impacts of synthetic biology on the conservation of biological diversity, it is important to take a realistic view, giving the complexity of the receiving environment. I see a risk of overestimating the potential of SynBio applications for nature conservation, with the IUCN report on this topic being a prominent example: Since the effects of genetically engineering wild organisms cannot be predicted in the long term, it is a matter of speculation whether the goals pursued with genetic modification could even be achieved. From a nature conservation point of view, the urgency of combating biodiversity loss is no reason to abandon the precautionary principle. Rather, the urgency of nature conservation issues justifies the implementation of effective measures to prevent the overuse and contamination of nature. There may therefore be considerably more useful and efficient investments of resources for nature conservation than promotion of SynBio research, that cannot deliver systemic solutions.

I addition – as already noted by the AHTEG in 2019 (CBD/SYNBIO/AHTEG/2019/1/3) these applications have conceptional challenges. To further specify these challenges the German Federal Agency for Nature Conservation (BfN) has recently published a position paper (https://bit.ly/gen-engin-conserv; DOI 10.19217/pos222en) on the question of non-contained LMO, i. e., LMO in wild populations, for purposes of nature conservation. In the course of our analysis for this viewpoint, we consulted all relevant Departments of the BfN, in particular those specialised in species survival and ecosystem protection and restoration. We conclude that the use of genetic engineering in wild populations does not hold a lot of potential for nature conservation. While we are of course in favour of substantial case-by-case analyses where this is possible (depending on whether the stage of development of an application allows sufficiently robust scenarios), we also argue that some points are of a more general nature. Thus, nature’s unique character– along with its diversity, beauty and utility – is one of the priority protected goods of nature conservation. The intrinsic value of nature’s unique character imposes limits on the extent to which humans can intervene in nature. Permanent, far-reaching and inheritable genetic modifications of wild organisms are contrary to nature’s intrinsic value and, in the BfN’s view, are not compatible with the current understanding of nature, with higher-level protected goods and with nature conservation objectives and practices

An important task of a safety discussion is to explore how SynBio itself may contribute owards overcoming existing and possible future biosafety problems by contributing to the design of safer biosystems, for example:
- Designing less competitive organisms by changing metabolic pathways;
- Replacing metabolic pathways with others that have an in-built dependency on external biochemicals;
- Designing evolutionary robust biological circuits;
- Using biological systems based on an alternative biochemical structure to avoid e.g., gene flow to and from wild species;
- Designing protocells that lack key features of living entities, such as growth or replication.


Gressel et al. (2013), for instance, discuss the environmental risk of spills of genetically modified microalgae used for biofuels production by physical containment and by genetically precluding the algae from replicating and competing in nature by introducing genes which severely decrease their fitness in natural ecosystems. Silencing or loss of such traits can be prevented by coupling them with a selectable trait such as herbicide resistance.

Dear colleagues,

I am Barbara Pilz, Campaign Manager at the non-profit Save our Seeds in Berlin, Germany. In the context of synthetic biology, my organisation has been particularly focused on highlighting the risks of potential environmental applications/releases of organisms containing engineered gene drives.

Some of the potential negative impacts vis-à-vis the three objectives of the Convention arising from such application include:

• Uncontrollability

Once released into the wild, a gene drive organism actively propagates in wild living populations and can rapidly spread over large distances. The unmanageable diversity of the natural habitats and ecosystems affected will make it massively more difficult to predict and control possible risks.

• Irreversibility

A gene drive causes a permanent genetic modification of the genetic material, which is passed on to all subsequent generations. Even if a gene drive encounters resistance and no longer spreads via its own mechanism of action, these changes are still inherited according to Mendel’s laws and continue to persist in the genome of the population for a long time. Only if the deactivated gene drive severely impairs the survival of the individuals would the mechanisms of natural selection, which could eliminate the changes in the natural populations, take effect.
Once released into the environment, gene drive organisms cannot be recalled nor controlled thus pre-empting and overriding the ability of nations, Indigenous Peoples, local communities and future generations to take their own decisions.

• Outcrossing across species boundaries

Gene drives are tailored to the genome of a single species, but in many cases outcrossing across species boundaries would likely be impossible to prevent.

• Unpredictability of CRISPR/Cas9

Many gene drives use the genetic engineering tool CRISPR/Cas9 to create a double-strand break at defined points in the genome. However, this tool does not work without errors. CRISPR/Cas9 can change the activity of the target gene in unpredictable ways, increase the mutation rate in the genome, lead to unexpected mutations or be disrupted in its function by emerging resistance.

• Resistance

CRISPR-based gene drives search for a clearly defined DNA sequence at which they should cut the genome. Even single mutations in this sequence can therefore make the target invisible to them. The organism thus becomes resistant to the gene drive. Such resistance can arise when CRISPR/Cas9 itself generates mutations that destroy the target sequence. However, they could also occur naturally, especially in populations with high genetic diversity.

• Unpredictable effects on ecosystems

Every living creature, even if it appears dangerous or harmful to humans, fulfils important tasks in its habitat. The extermination or even manipulation of a species will therefore have consequences for the entire ecosystem.

Current levels of scientific understanding are not sufficient to predict the potential impacts on biodiversity at the many different layers of all the complex ecosystems in time and space that gene drive organisms would interfere with. Gene drives open the door to wide-scale genetic engineering of wild species, which is at odds with the objectives of the Convention and raises fundamental ethical questions regarding the role of humanity in natural evolution.

More detailed information can be found here:
https://www.stop-genedrives.eu/en/ecological-risks/
https://www.stop-genedrives.eu/en/manifesto/

Hello again dear colleagues! I recently introduced my self. I am Frederic Ngezahayo from "Ecole Normale Superieure" in Burundi.

Thank you so much for varried important informations shared here on synthetic biology. Beside the possible societal postive impact of synthetic biology, I think that potential negative impacts of Synthetic biology needs to be addressed because of possible horizontal of vertical transfer of transgens to wild or domesticated populations. This may lead to decrease in genetic diversity in the actual loss of biodiversity.

MacFarlane et al.2022 recently reviewed Direct and indirect impacts of Synthetic biology on biodiversity conservation (see attachment).

Greetings again colleagues
What fascinating and energising discussion thanks to you all.

I would like to extend my appreciation in the waning moments of the forum to those raising the issue of 'natural' (and 'foreign' [#2724]) in the context of biotechnology. As Dr. Steinbrecher [#2730] said, natural has a triple use in some discussions. It is at once a reassurance that something is no greater a threat than what we are used to, that natural is a quality that can be verified and measured as an outcome of a scientific process, and it is only fair that the activities of people should not be held to a higher social standard (eg via regulation) than to which we hold spontaneous events outside our instigation.

No technology is natural no matter how much in some ways it may mimic spontaneous events. A critical fission nuclear reaction is at one level still a series of atomic decays as happen in the dessert of Australia all the time. The technology for making nuclear power plants or bombs is also 'natural' in this regard, but very unnatural in regard to the three issues I raise above. For those with a greater interest in this topic, we also wrote about this in The Conversation https://theconversation.com/calling-the-latest-gene-technologies-natural-is-a-semantic-distraction-they-must-still-be-regulated-166352 and in https://doi.org/10.1525/elementa.2021.00086 and in A Bigger Conversation https://abiggerconversation.org/genetic-technologies-safety-and-risk-correlate-with-scale-not-naturalness/.

Dr. Antonsen [#2732] also among other things discusses how 'natural' is a normative conclusion that arises from cultural lenses. Conclusions of natural are inextricably linked to what we choose to leave unknown (or excluded), in the words of Agapito-Tenfen et al (http://dx.doi.org/10.3389/fpls.2018.01874). This point and many others about the discourse on naturalness was examined by Yoshiki Otsuka who observed the transition to acceptance of natural in the discourse of technology producers. She wrote "the consumer movement considers it ironic that the breeding process and the concept of 'naturalness,' which was once criticized as nonscientific, have become a valid scientific justification for the exemption of genome editing in regulation of GMOs." https://doi.org/10.1080/18752160.2021.1877442

I apologise if I have yet to read other interventions on this topic. Many have come in overnight my time!
Jack

Greetings again!

Dear online forum participants,

My name is Felicity Keiper and I am participating in this forum as a representative of the Global Industry Coalition (GIC). We have commented on Question 1(a), and for this question wish to support comments highlighting that synthetic biology applications, and the enabling technologies used, are not inherently risky (e.g. #2661, #2673, #2678, #2711), and that risk needs to be assessed on case-by-case basis (e.g. #2595, #2690, #2692, #2705, #2711). We also agree with suggestions that positive impacts (i.e. benefit assessment) could contribute to regulatory processes (e.g. #2661, #2711, #2743), as well as consideration of the impacts of current/alternative options (e.g. #2569, #2614, #2678).

We continue to disagree with the inclusion of genome editing as “synthetic biology”, particularly where it is used in plant breeding to generate mutations that are equivalent to that achievable with conventional tools. The lack of scientific basis for this is emphasized in #2743, and the implications of this “mixing up” for acceptance of the technology recognized in #2709 and #2718. We have submitted at length previously in this work under the CBD that genome editing is an enabling tool that can be used to achieve various outcomes, and where these outcomes are GMO/LMO, they are within the scope of existing regulatory mechanisms. We therefore do not agree with the focus on genome editing in the trend of “increasing sophistication of methods” – we also question the relevance of the “trend” itself (see our comments for Topic 1, Question 2).

Comments are made in this thread regarding genome editing in association with the “trend” of “increasing sophistication of methods” that we wish to address. These include the inference that technological developments lead to “negative” impacts/greater risk due to increasing complexity/magnitude of human intervention (e.g. #2636). This is a simplistic assumption; technological developments are aimed at improved efficiency and predictability of outcomes (as recognized in #2661 and #2743) without necessarily creating new “issues”. In other comments there are assertions of a “push to deregulate” (#2639 and #2643), and that “deregulation” is justification for inclusion in horizon scanning (#2617), along with criticism of “tiered” regulatory approaches. We emphasize that a tiered approach is consistent with a case-by-case approach to regulation that is proportionate to risk. Further, such an approach is consistent with the fundamental principles of risk assessment established by the Cartagena Protocol, and these continue to apply to synthetic biology. Where an application is determined not to be within the scope of GMO/LMO regulation, this is based on an assessment of evidence by a competent authority that the outcome does not present novel risk.

Regards,
Dr Felicity Keiper

Dear participants,
my name is Marcelo H A Freitas, I am a virologist and my specialty is gene and protein expression control/molecular signaling. I work at the Brazilian Agricultural Research Corporation (Embrapa), member of the National Technical Commission on Biosafety (CTNBio) in Brazil and I follow discussions and negotiations related to scientific research in various international forums and initiatives (CBD, FAO, ITPGRFA, CGR,...).

I would like to reinforce the assertions of colleagues Carolina Villafañe (2635), Mr. Lasse Middendorf (2661), Mr. Heinemann (2639), Mr. Pieter van der Meer (2673), Ms. Luciana Ambrozevicius (2700) and Bong Hyun Sung (2705).

As we mentioned before, we can use all the work, experience and framework developed for LMOs for Synbio. After all, like Mr. Pieter van der Meer (2673) put it, all organisms developed using Synbio are within the scope of the Cartagena Protocol on Biosafety.

We also agree that an adequate risk assessment, based on scientific facts, with well-defined and case-by-case criteria can be used to predict possible positive and negative impacts of a product developed using Synbio.
However, what I do notice and am concerned about is that in various CBD discussions and negotiations, biotechnology, including Synbio, appears to have an inappropriate concern for negative impact. Positive impacts seem not often considered or minimized.

----Posted on behalf of Dr. Martin Cannell---

Dear Participants,
I would first like to thank you for your thoughtful exchange on both the potential positive and potential negative impacts that the applications of synthetic biology may have on the three objectives on the Convention, as well sharing helpful sources for obtaining more information. It is clear that we will need to keep in mind that these potential impacts will be on a case-by-case basis for each of the applications and the context of their use. Further, there will likely be uncertainty with regards to these potential impacts. That being said and without going into the specific examples, several potential impacts in the areas of carbon fixation, conservation, ecosystem services, health and intellectual property rights, as well as the potential for dual-use of the technologies, were mentioned by various participants. In different manners, these may support or counteract the conservation and sustainable use of biological diversity, as well as the access and benefits sharing of genetic resources. Overall, decision-making will need to account for the risks and, depending on national legislation, the benefits and socioeconomic considerations, when considering these applications. I will work with the Secretariat to compile these elements in the report of the online discussions for consideration by the multidisciplinary AHTEG.
Best regards,
Martin