Past Activities 2019-2020

Dear Forum participants,

Discussions under topics 1 and 2 were very interesting and provided important information. We now have ahead of us another challenge, this time to discuss topics 3 and 4.
I will welcome your comments under this topic and will take the opportunity to kindly remind you to please refrain from creating new threads. Instead, please reply to the thread initiated by this message. In addition, if you intend to reply to another comment, please make sure you indicate the # of the post you are replying to.

This week’s discussion will focus on possible impacts of synthetic biology applications that are in early stages of research and development, on the three objectives of the Convention. This will support the deliberations of the AHTEG on the preparation of a forward-looking report as per item (e) of its terms of reference.
Considering that organisms, components and products of synthetic biology could pose positive and negative impacts on the conservation and sustainable use of biological diversity, the aim of this forum is to point out some of these impacts and share evidence or information that supports these potential impacts.
I propose the sharing of new information related to this topic; for example, what information exists related to organisms that have been developed to contain engineered gene drives, in the light of the impacts that such organisms might have on the conservation and sustainable use of biological diversity?
Can we envisage some positive or negative impacts of the use of organisms, components and products of synthetic biology? Is there any evidence that support these impacts?
Your contributions will promote an enriching discussion on these topics that are vitally important when speaking of synthetic biology in light of the three objectives of the Convention.
When posting the information, participants are requested to provide their source of information, indicating if it is coming from a publication, their own work, or other type of source.

Thank you,

Maria de Lourdes Torres

Dear Maria,

Thanks for your moderation.

I have a quick comment. From my point of view, the impact of synthetic biology on the three objectives of the Convention has two main aspects; one is affecting biodiversity conservation and sustainable use through impacting the organisms (habitats) in nature. For instance the escape of gene driver (e.g. CRISPR-Cas9) that aims to eliminate certain pests may also eliminate other wild related species in the ecosystem. In this aspect, as our colleagues mentioned during previous discussion (topic 1&2), there will be a report of assessment released soon on synthetic biology and biodiversity conservation by IUCN. Another aspect is on the access to genetic resources and benefit sharing as the digital sequence information is sometimes enough for the utilization of genetic resources with no physical materials required.

Best wishes

Wei

I agree with interventions  #9487 Wei Wei, #9499 Delphine Thizy, #9506 Gernot Segelbacher and #9509 Risa Smith. I think that potential ecological consequences of deliberate releases of gene drive organisms into environment would be very relevant, especially in countries as Mexico which are center of origin and diversity.

Definitely the analysis must be doing case by case but there are a lot of possible consequences that we don´t know. One important factor taking into account is the ecosystems resilience if we introduce new organisms in an abrupt way.

I think maybe we can learn some lessons from invasive species.

In my previous Post (#9386), I referred to how distinct interpretations of “material” in the Convention on Biological Diversity (CBD) would preclude any agreement on Topic 4. At the 14th Conference of the Parties (November 2018 Sharm-El-Sheikh), delegations from the European Union and Switzerland, among others, took the position that “genetic material” was “tangible”, which would place “digital sequence information” (DSI) out of scope for the third objective of the CBD.

An unintended consequence is that “...the understanding, design, redesign...and/or modification of [DSI]” would no longer be Synthetic Biology, according to the AHTEG definition.

Dear colleagues

Unfortunately I was unable to attend the meeting in Egypt so thank you Joseph for this post. I am curious about the concept of tangibility. Applied literally, this would exclude DNA and all microbes and some seeds from scope. If on the other hand DNA and microbes are tangible, then so are the materials in which DSI is stored or through which it is transmitted. DSI is always in some material form.

Regards
Jack

I am gree with the remarks of Wei and Jack and consider important to consider the DNA and microbes as part of "tangeble" items.

It might be useful as well to bring on board the conclusions of the discussion on the symposium on SynBio under the OECD: http://www.oecd.org/sti/emerging-tech/45144066.pdf

Regards,
Angela Lozan

In response to the discerning question of Post #9491.

The adjective “tangible” does not modify “genetic material” in either the CBD or the NP.  Thinking like an economist, the interpretation of tangibility for “genetic material” would incentivize DSI to avoid  ABS. The Peruvian Society of Environmental Law elaborated the argument in “Lawful Avoidance of ABS: Jurisdiction Shopping and Selection of non-Genetic-Material Media for Transmission” in response to “Proposals for new and emerging issues for SBSTTA-21 and COP-14” (SCBD/OIC/DC/RH/84326) (1 May 2017: available at https://www.cbd.int/doc/emerging-issues/SPDA-submission2017-05-en.pdf and also in Spanish at:  https://www.cbd.int/doc/emerging-issues/SPDA-submission2017-05-es.pdf)

However, if “genetic material” is interpreted as inclusive of “information”, then DSI would appear to fall within the scope of ABS.

I appreciate very much this opportunity that COP had mandated the online form and the AHTEG to discuss issues on synthetic biology (SB). As there is no decision yet published, those questions still remain open for discussion, including the definition of SB and DSI. The new AHTEG has to take this opportunity to improve the work and to update the knowledge in a scientifically sound manner.

In the era of information and internet, we can never assume 'information' as non-tangible. I think that the DNA and RNA sequences that composed of genetic codes and nucleobases will be certainly tangible. A published FAO report (http://www.fao.org/3/CA2359EN/ca2359en.pdf) called for that DSI shall be included in genetic material whether or not tangible.

In addition, I believe that DSI would fall within the scope of ABS. Anyway, it is not righteous to encourage intended avoidance of ABS, whether lawful or not.

Best wishes

Wei

Dear Maria，

My views have been posted in the Topic 3. I would like to share it here again since it is also relevant with this topic.

In my view, synthetic biology is a kind of combinations of many technologies. The application of synthetic biology have been increase recently all over the world mostly for industry and medince use, such as fermentation and surgery. These applications are no negative evnironmental impacts, but postively contribute to the sustainable use of biological resources and human health. However, there are a few cases reported regarding the manufacturing of Cyanobacteria, which have potentials to release into environment. In such case, negative environmental impacts would be found.


In general, I am of the view that the impacts of synthetic biology should be considered case by case with identifing whether or not certain Synbio technology have potential to release into the environment as a very first step, which can help us to understand the right picture for Synbio.

Thank you.

Dear Maria,

Thanks for your moderation.

This is Zhiwen Wang from Tianjin University. My research interest focus on development of genome editing system like CRISPR-Cas9, construction of microorganisms for biotechnological applications by metabolic engineering and synthetic biology. From my point of view on impact of synthetic biology, it is really a powerful technique for us to construct microbial cell factory. It also has potential negative impacts on the conservation and sustainable use of biological diversity. The gene escape may occur for the organisms that have been developed to contain engineered gene drives. Fortunately, the synthetic biology scientists are developing some methods or tools to eliminate the modification system like CRISPR-Cas9 component or kill micorganisms before release in to environment. I am thinking that currently the organisms contain engineered gene drives should be maintained in closed system (for instance fermenter) rather than open system to protect the conservation and sustainable use of biological diversity. With the development of synthetic biology, I almost make sure we can handle this technology to make full use of its advantage and protect biological diversity as much as possible.

Best wishes

Zhiwen

Hello every one, I am Felicien AMAKPE (PhD), the National Focal Point of the Cartagena Protocol of the Republic of Benin.
I thank the respected participants and the moderators for giving me the opportunity to participate in this discussion where I am learning a lot.
The great concern to Biodiversity losses are not only related to the fact that they affect ecosystem functions on earth, but they also adversely impact the vital services for human societies and pollination which is critical to fruit and seed production. The live pollinators (insects, mammals, birds) are to my mind one of the most important agents on which we should target our investigations when dealing with the possible impacts of synthetic biology applications. As pointed out by Wei in post #9487 and other posts ([#9442], [#9392], [#9380]) many applications of nitrogen fixing gene-edited bacteria and gene-edited Bacteria/ viruses in agriculture and for biological controls may potentially impact pollinators, especially the bees in their search for nectar, pollen or propolis. I would like our cherished participants to send us uptodate information and relevant publications on this issues.
Best regards
Amakpe

Jack A. Heinemann et al find in their 2018 FAO study, cited in Post #9497, that “[t]he shift in the value of DSI is more and more uncoupled from a source biological material” (p. 58). Indeed, “digital sequence information” is prima facie intangible. They also show that the place that DSI holds among scientists is none: “[T]he scientific community notably does not use the term DSI (Figure 3)” (p. 9 and 10). Also relevant is their conclusion that “there may be little value in a simple and precise definition DSI that is disconnected from the complex and evolving practices of the bioinformatics and synthetic biology communities.” (p. 69) An implication, perhaps unintended, is that there may be great value in a simple and precise term, not necessarily DSI, which allows for the complex and evolving practices of the bioinformatics and synthetic biology communities.

The sentiment expressed in Post #9497 is truly admirable.  Lawful avoidance of ABS should not be encouraged, which has unfortunately been the case due to the deficient or missing definitions and unusual interpretations of specific language in the CBD and NP.

Dear all,
Thank you for the rich conversation and to our committed moderator!
My name is Delphine Thizy, I am the stakeholder engagement manager working at Imperial College London for Target Malaria (http://www.targetmalaria.org), a non-for-profit research consortium working to develop and share innovative vector control tools to reduce malaria vector with genetic approaches and in particular engineered gene drive mechanism. I also have the honour of being part of the IUCN (International Union for Conservation of Nature) task force on synthetic biology.

My contribution is more specifically on engineered gene drive applications’ potential impacts on the Convention’s objectives and more broadly on the Sustainable Development Goals. Engineered gene drive mechanisms are diverse and two main types of applications can be identified: those directly aiming at conservation objectives and those that could have indirect impacts on conservation. In the first category, the applications currently under review are trying to mitigate threats (e.g. fighting invasive species), but applications to increase species resilience could also be envisaged. In the second category, the applications that are currently most advanced are related to public health and vector control. As Dan Tompkins said in a previous intervention, the IUCN report resulting of the task force on synthetic biology is due to be published very soon and should provide a good overview of applications currently considered, their progress, as well as a review of their potential impacts. This report (amongst other initiatives) will provide important perspectives for the conservation community.

Target Malaria is one of the research groups working on the public health applications of gene drive for vector control. Our approach is to target specific mosquito species, known to be the main vectors of malaria in Africa (Anopheles gambiae species complex), to reduce their population and thus complement existing tools. According to the World Health Organisation 2018 World Malaria Report, 435.000 people died of malaria in 2017, of which 92% in Africa. The existing tools (treatment, long-lasting insecticide treated bednets, indoor residual spraying) have contributed to reduce the number of deaths over the last decade, however the progress has stalled and there are now risks of resurgence, and already increases of cases in the 10 highest burden countries in Africa. Faced with this crossroad, the malaria community and experts are calling for renewed investments (such as the commitment made by the Commonwealth countries in 2018) including the development of new tools to complement existing ones and accelerate the elimination of malaria.

Target Malaria is engaged in research that aims to address many of the barriers identified in the WHO’s Global Technical Strategy for Malaria by exploring the use of gene drive approaches for vector control. Target Malaria’s research encompasses both technical and scientific aspects of the prospective technologies, as well as considerations related to its eventual evaluation for efficacy (such as stakeholder engagement and regulatory compliance). The research in the laboratory (Kyrou et al., 2018) as well as modelling (Eckhoff, Wenger, Godfray, & Burt, 2017) show that this technology has the potential for positive impact on public health (African Union, 2018), and thus contributing to the SDG 3 on health. Field evaluation of gene drive mosquitoes is still many years away for Target Malaria but this research is already ongoing important and regular review from WHO with the Vector Control Advisory Group (WHO, 2017, 2018).

As highlighted in the decision on synthetic biology made at COP14, which is aligned with conclusions from other reports (Australian Academy of Science, 2017; National Academies of Sciences Engineering and Medicine, 2016; Royal Society, 2018; Society, Apārangi, & Editing, 2017, African Union, 2018) engineered gene drive technologies will need to be evaluated on a case-by-case basis. Different applications and context might require different gene drive constructs and thus it is important to look at specific cases. Researchers and experts are already exploring how responsible evaluation of this technology can be carried out (James et al., 2018).

Dear all, dear Maria,

I would like to focus on the questions as proposed by our moderator, which are:

1.What information exists related to organisms that have been developed to contain engineered gene drives, in the light of the impacts that such organisms might have on the conservation and sustainable use of biological diversity?

2.Can we envisage some positive or negative impacts of the use of organisms, components and products of synthetic biology? Is there any evidence that support these impacts?

Since these questions are closely linked to the question under topic 3, I consider my reply also to be applicable to topic 3.

To answer question 1. What information exists related to organisms that have been developed to contain engineered gene drives, in the light of the impacts that such organisms might have on the conservation and sustainable use of biological diversity?

My answer would be that at this moment there is no existing information on impacts on the conservation and sustainable use of biological diversity from organisms containing engineered gene drives. As stated before, organisms that containing engineered gene drives may have both positive and negative effects on biodiversity. Effects can only be assessed based on a case-by-case environmental risk assessment, taking into account aspects such as the specific organism and it dissemination, the introduced trait, the receiving environment, type of application but also the type of gene drive system (low threshold, high threshold gene drive). 
Information that may be relevant to potential impacts of organisms with engineered gene drives, is information available on environmental impacts of invasive species, biological control agents (such as insects) that have been released in the environment to suppress pests, information from applications of the sterile insect techniques to suppress mosquitoes, or from experience with insects genetically modified to suppress populations, or Wolbachia-containing insects. Some inforamtion can be found via the links below:
https://onlinelibrary.wiley.com/doi/10.1002/9781119255574.ch5
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946175/
https://www.sciencedirect.com/science/article/pii/S2214574515000905
https://onlinelibrary.wiley.com/doi/full/10.1111/eva.12286

In addition, in 2017 a literature report was commissioned by the Dutch Committee of Genetic Modification  (COGEM) titled  ‘Gene drives-Experience with gene drive systems that may inform an environmental risk assessment’. The final report will soon be published on the COGEM website https://www.cogem.net/index.cfm/en/publications/

To answer question 2. Can we envisage some positive or negative impacts of the use of organisms, components and products of synthetic biology? Is there any evidence that support these impacts?

For this we can draw on experience obtained with the use of LMOs and their products, given the fact that almost all organisms obtained by synthetic biology so far fall under the definition of an LMO. The same positive and negative effects may therefore be envisaged by organisms, components and products of synthetic biology. Few additional hazards have been identified for some further developments in synthetic biology, such as those identified by the SCENHIR, in their scientific opinions https://publications.europa.eu/en/publication-detail/-/publication/9b231c71-faf1-11e5-b713-01aa75ed71a1/language-en  Examples are potential toxicity of protocells or potential negative effects resulting from the use of XNA instead of DNA in organisms (xenobiology). Since these developments are still in an early phase, there is no evidence to support potential impacts of these applications.

Kind regards,
Boet

I agree with Boet's perspective (#9500) that there is existing information that is relevant to assessment of potential impacts of organisms with engineered gene drives. Risk assessment approaches for non-LMO biological control agents and exotic species may be informative for risk assessment of organisms containing engineered gene drives.  For example, risk assessment guidance and processes used for assessing risks involved in releasing wild type biological control agents designed to eliminate or eradicate an invasive alien species would have similarities to the assessment of an engineered gene drive organism for population control.

Best regards,
Louisa

Dear all,

Under topic 4, I already contributed some publications regarding possible negative impacts of SynBio applications on the environment and the goals of the convention. These publication are especially relevant for assessing negative impacts on biodiversity and the environment due to unintended effects which are triggered by ‘genome editing’. If interested, please read my submission under topic 4.

In addition, under topic 3, I attach a new report of Testbiotech which deals with regulatory aspects of genome editing. It also can be found at: http://www.testbiotech.org/en/content/am-i-regulated-en

The report shows the need for detailed risk assessment of SynBio, genome edited organisms. The United States Department of Agriculture (USDA) has already given non-regulated status to more than 20 plants genetically engineered with so-called genome editing techniques. None of the applications registered at USDA were referred for further more detailed assessment. The Testbiotech report shows that there are however significant differences in methods of production, traits and risks of the non-regulated plants in comparison to those derived from conventional breeding.

These differences are not caused by the newly introduced gene sequences but by e.g. the patterns of genetic changes. ‘Gene-scissors’ such as CRISPR/Cas can delete whole families of gene variants all at once - this is either impossible or barely possible with current conventional breeding methods. A further specific difference: in a first step, older methods such as the ‘gene gun’ (biolistic method) or gene transfer via agrobacterium tumefaciens are commonly used. However, USDA completely ignores these differences to conventional breeding.

Essentially, conventional breeding is always based on a wide range of genetic and biological diversity found in natural populations, as well as in all previously bred plant and animal varieties and breeds. In addition, new mutations happen continually and specific triggers can speed up the occurrence of mutations. Not all of these mutations are considered beneficial. In order to achieve the desired results, breeders screen natural populations and previously bred varieties for specific traits. Subsequently, plants are chosen and then grown and crossed to achieve an optimal combination of genetic information. The natural mechanisms of inheritance and gene regulation cannot be bypassed with this method.

Genetic engineering on the other hand uses direct technical and targeted intervention to establish new traits. These technical interventions bypass natural biological mechanisms governed by evolution, inheritance and gene regulation, and can therefore be much faster than conventional breeding. Since genetic engineering intervenes directly in the genome, the resulting plants and animals can be very different to those from conventional breeding. Therefore, it is necessary to treat these organisms with caution before any environmental releases take place or they are approved for use in food production.

In summary, the risks of such genetically engineered organisms have to be assessed in each and every case. Moreover, if organisms are known to show potential for environmental spread or might develop such characteristics, efficient measures and restrictions have to be put in place to prevent gene flow.

with kind regards

Christoph Then

My name is Luz Stella Barrero. I want to thank Maria and everyone for the interesting discussions. I am a research scientist at the Colombian Corporation for Agricultural Research and I have been working in collaborative projects with Cornell University and University of Minnesota using CRISPR/cas9 to modify alleles at genes of interest for the improvement of cereal crops. Without having a clear definition of synthetic biology, as has been discussed in the forums, this application would fall into synthetic biology that comprises the re-design of existing biological systems i.e. additional improvement of existing materials cultivated by farmers. Releasing biological products made from synthetic biology may have positive impacts on the environment, human health and food industry depending on the application (case by case, in agreement with intervention #9494), and it is more justifiable when traditional breeding cannot achieve the goal and cannot be as timely effective and precise as synthetic biology. In several cases the benefits might outperform the pitfalls since it has been demonstrated it can improve food quality, yield, biotic or abiotic stress tolerance in several species, with potential benefits to human health and the environment i.e. fewer chemical inputs to sustain agriculture. It should be of less concern if product is free of foreign DNA before releasing to the environment (in agreement with intervention #9495) and if product is probably indistinguishable from traditional breeding.

Here are some links of interest:
https://www.nationalgeographic.com/environment/future-of-food/food-technology-gene-editing/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952327/

Dear all,
Thanks for the discussion. As Delphine mentioned  (#9499) quite a few points will be listed in the assessment when it comes to potential applications and their effect on biodiversity.
More specifically to question 2: I wonder to what extent we have to consider indirect effects. On the Genetic Literacy project you can find quite many examples (such as companies creating leather de novo, lab grown meat, etc...) https://geneticliteracyproject.org/category/synthetic-biology .
Obviously changes in diet and animal consumption will highly effect landuse and might be also of some relevance here.

POSTED ON BEHALF OF Ms. Risa Smith, IUCN/World Commission on Protected Areas:
********************
Thanks to the moderator for the excellent forum. My name is Risa Smith.  I am co-chair of the IUCN/World Commission on Protected Areas/Climate Change Specialist Group. 
I am responding to the moderator’s question: Can we envisage some positive or negative impacts of the use of organisms, components and products of synthetic biology?  These comments represent my own thoughts and not the position of IUCN and will have an effect on two of the three objectives of the convention: conservation and sustainable use.
In response to #9506 , Gernot Segelbacher raises the issue that “… changes in diet and animal consumption will highly effect landuse …”.  I agree with this comment and believe that synthetic biology is a transformational technology that could have very significant effects on the way that we produce protein.  For example, synthetic proteins could replace milk and beef and possibly fish.  If they become socially acceptable they will result in a significant decline in the global consumption of milk from dairy and meat from livestock.  Currently the methane produced by enteric fermentation of ruminants is an important greenhouse gas emission, as is the conversion of forests to agricultural land for beef and dairy production.  The use of synthetic proteins could result in a reduction in GHG emissions from agriculture and improvements for the biodiversity that is harmed by conversion of natural systems for meat and milk production.
There are many other applications of synbio in agriculture that are either in the research stage or already viable.  Many of these applications address the environmental impact of agriculture on biodiversity (e.g. engineering plants to produce nitrogen, thereby reducing the use of fertilizers).  We already have companies producing beef-free hamburgers, cheese from a synthetic substitute for milk, eggs without chickens etc.
Like all disruptive technologies, synthetic biology is allowing us to solve some significant environmental issues, including conservation issues, but we will have to find ways to transition to these types of technologies so that livelihoods can be replaced.  To me this topic of synthetic biology as a major disruptive technology is the ‘elephant in the room’ in discussions at the CBD.
There are several reviews that touch on the relationship between synthetic biology, agriculture and biodiversity.  One of several is: Goold, Wright and Haistones, 2018.  Genes 9, 341 https://www.mdpi.com/2073-4425/9/7.341/pdf

I fully agree with the positions taken and the examples used by Ms Risa Smith (IUCN - post # 9509), Boet Glandorf (Netherlands, post # 9500) and by Bob Friedman (Craig Venter Institute - post # 9510).

Dear Maria,

Thank you for your brilliant moderation.

It is noteworthy to state that the up sides of SynBio in technological developments outweighs the down sides. This is because it has offered scientists a new approach of resolving challenges in energy, human health and environment.
                                                                                                                       
The relative novelty of its application has made full assessment of environmental impact of SynBio difficult. This is because of the limited information available in the field. However, a few literature available point to a possible environmental implication of Blue algae (Cyanobacteria engineered for the photosynthetic production of fuels, fine chemicals, and proteins from CO2).

Supporting the post #9493, I am of the opinion that case-by-case approach, as recommended in the Cartagena Protocol on Biosafety, be used to determine environmental impact associated with Symbio events.

Thank you.

Chinyere Nzeduru
NBMA, Nigeria

Maria posed the following
Q1. what information exists related to organisms that have been developed to contain engineered gene drives, in the light of the impacts that such organisms might have on the conservation and sustainable use of biological diversity?
A1. In response to this I refer to the upcoming reports referred to by Boet and the comments of Delphine Thizy.  The ecological impacts of gene drive will obviously be case specific and depend very much on the nature of the target species, its niches in the food chain and roles in ecosystems, the ecosystem services it provides, the species affected by its removal and the species that will replace it . In addition if gene drive is replacing other control measures, the environmental effects of this substitution may be significant.  Balancing the local or regional extinction of a species against the benefits of disease control requires careful consideration of social, cultural and ethical factors together with the health benefits.
Q2. Can we envisage some positive or negative impacts of the use of organisms, components and products of synthetic biology? Is there any evidence that support these impacts?
Theoretically we can envisage almost any new biological or biochemical product being produced by synbio and the creation of a new range of cellular organisms. Ultimately in combination with other forms of technology such as nano tech, prosthetics, robotics etc., new organs and body parts for higher organisms can be made with modified genetic coding. Thus we could develop non ageing stem cells, regenerating nerve and brain cells, infrared and ultra-sonic perception in humans etc.... In terms of negative impacts, these will be case by case and also depend on how the new products are utilized and exploited. Initially SynBio will be restricted to microbes which will be largely grown in bioreactors with minimal environmental exposure and impact. The impacts of the bioreactors, the processes being replaced, and the novel products will be the main subjects of any assessment. If synthetic microbia are released then the impacts become harder to assess as there has been no in vivo experience of their environmental interactions. Alien species have usually been studied in their countries of origin. However there will be no such experience with synthetic organisms and some will not have conventional counterparts to act as comparators. Thus determining impacts will depend on environmental studies with surrogates and surrogate comparators to determine relative fitness characteristics, initially in environmental simulations.

Dear all—

I am Bob Friedman, a researcher with the J. Craig Venter Institute (JCVI), a non-profit genomics research institute with an active synthetic biology research portfolio.  JCVI does not do any research on gene drives, but I also work with scientists at the University of California, San Diego and University of California, Irvine who are actively developing mosquitos modified with engineered gene drives.

My thanks to our moderators and to all for the informative discussions so far.  Delphine Thizy [#9499] and Boet Glandorf [9500] provided very helpful discussions about, and listing of key literature on, engineered gene drives.  Delphine eloquently presents the potential benefits to be gained from gene drive applications currently under development to control malaria.  Boet emphasizes that positive and negative impacts can only be determined on a case-by case basis, but that relevant information is available from currently available methods of vector control.

I would like to point out an alternative approach under development by colleagues at UC San Diego and UC Irvine, first published in 2015.  Rather than trying to suppress the population of mosquitoes (in this case Anopheles stephensi), why not design a gene drive to suppress the disease-causing parasite (Plasmodium) that the mosquito carries?  (Gantz et al., 2015, https://doi.org/10.1073/pnas.1521077112)

This alternative approach is called a “replacement drive”.  These researchers are developing a gene drive containing mosquito that includes a gene that makes the mosquito resistant to carrying the parasite, thus breaking the deadly chain of transmission from mosquito to human to mosquito.  If successful, a disease-carrying population of mosquitoes would be replaced by an otherwise almost identical population of mosquitoes that cannot transmit malaria.

It is important that multiple approaches are explored and developed, so that appropriate technologies might be applied to fit the specific problem and circumstances being addressed.  In situations where there is concern about ecosystem-level effects from suppressing the population of a species, “replacement drives” may be a preferred approach.

Regards,
Bob Friedman

Dear Forum Participants,

Thank you for the lively conversation under Topic 4: Possible impacts of synthetic biology applications that are in early stages of research and development on the three objectives of the Convention.
Many of your contributions are trying to correctly identify the possible impacts of synthetic biology applications on the objectives of the Convention. Nevertheless, sometimes it is difficult to foresee the possible impacts of these new developments, since many of these are indeed in early stages of research and development.
The main objective of this forum is to make a compilation of what is known until now about the possible impacts that the application of synthetic biology may have on the conservation and sustainable use of biodiversity. In this sense, I appreciate the efforts made in this forum to highlight both positive and negative impacts.
I also welcome participations that have invited us to stay focused on this topic and try to answer the questions posed by the moderator. These guiding questions attempt to organize this debate with the goal of gathering relevant information that could serve for the meeting of the AHTEG.
In closing, I have noticed that several messages are referring to DSI. This topic is undoubtedly relevant for the Convention and its discussions are taking place under the Nagoya protocol. So, I kindly request the participants to keep in mind that DSI deliberations are not part of the COP discussions under synthetic biology, and thus, interventions in this forum may want to refer to DSI in direct relation to Synbio applications.

Thanks again for your enthusiasm in contributing to this forum and I look forward to your interventions until the end of this forum

Best Regards,

Maria

Dear Maria,

After reviewing the interventions made by distinguished participants. I think there are two issues on the table.
One is possible DIRECT impacts of synbio applications that are in early stages of research and development on the three objectives of the Convention, and second is INDIRECT impacts as such.
My suggestion is we should address these two questions one by one. After reviewing interventions made by other distinguished participants. I do see many potential benefits to apply synbio for human health and sustainable use of resources. Having said that, I also concerned about the risks for applying of synbio in environment. In that sense, I think the director impacts of synbio should be evaluated for those organisms will be released into the environment.
For those indirect impacts, such as the application of DSI, I think this is also very important issue, and I agree with that such issue could be addressed under other discussion process.

Best regards

Reflecting on the possible impacts of synthetic biology applications that are in the early stages of research and development, I have been interested to read the discussion about potential future impacts (eg from system-wide changes to protein production, as described by Melissa #9509). From my perspective in a regulatory agency I consider it is also necessary to recognise the limited current impact of the research and development activity from which these long-term scenarios arise, because the work is being undertaken in containment facilities. The biosafety field is a well-established discipline which has been in existence for more than 30 years and has considerable experience in the containment of organisms, resulting in a large field of information available internationally on the requirements for safe containment of organisms in research and manufacturing (also relevant to topic 3). For this reason, in discussing potential positive and negative impacts of synthetic biology it is important to distinguish between activities in controlled, contained facilities and the environmental release of organisms derived from synthetic biology. This distinction has already been noted by Jeremy (#9507) in relation to production in bioreactors.

Returning to the possible future impacts, it is worth keeping in mind that there are already mechanisms to assess and manage risks from environmental release of synthetic biology organisms that are also LMOs. I anticipate topic 5 will provide a useful perspective in this regard.

Best regards,
Louisa

I fully agree with the sentiments of Bob Friedman (#9510) where he stresses the need for consideration of novel synbio or use of LMOs on a case-by-case basis. An extensive appraisal of the risks and benefits in any potential scenario is essential. For novel technological approaches  in this field there can be a tendency to only focus on trying to find hypothetical pathways to how something could go wrong, whereas there are several global health challenges where these technologies could provide solutions to huge problems that have previously been intractable.

Dear all,

I am Austin Burt, Professor of Evolutionary Genetics at Imperial College London and Principal Investigator of Target Malaria, a not-for-profit research consortium looking to develop new genetic approaches to control and eliminate malaria (http://www.targetmalaria.org). 

"Gene drive” has been mentioned a couple times already in this topic (and also topic 3), and I would like to briefly share my perspective on this subject. For me it is important to understand that gene drive is not a single thing, but more of an umbrella term under which there are many possibilities. There are low threshold drives, high threshold drives, integral drives, split drives, daisy drives, daisy field drives, tethered drives, and sex-limited drives, and the list continues to grow. Many of these use much the same molecular tools (e.g., CRISPR/Cas9 nucleases), but the arrangement or configuration of these tools differs, which means they would behave differently in a population. Indeed, there’s no widely accepted definition of what exactly constitutes a drive system — it has become a bit of a buzz word, as is common in new, active fields of science.

About the only things they do have in common are

1) they are LMOs — there is no ambiguity as with some edited organisms where only a single base pair has been changed — and therefore they would be regulated as such by existing modified organism regulations;

2) they involve modifying the transmission or inheritance of genes from one generation to the next; and

3) they are directed at controlling pest species of one sort or another (rather than engineering microbes in bio-reactors or crops in farmers’ fields, which have been the primary focus of non-academic LMO work thus far).

One other thing that many of these strategies share is that they have not yet even been demonstrated in the lab, but instead have only been demonstrated in computer simulations. It’s a very young field, with lots of ideas bubbling up, and that is likely to continue over the coming years, with researchers suggesting novel genetic approaches that have not yet been thought of. That needs to be taken into account in thinking about policy — one would not want to choke off this highly fertile period when we are still learning about the potential capabilities of this new field. That said, safety obviously has to be paramount, and there is good guidance available (from scientists and other groups and the existing regulatory framework on contained use) on how to conduct this research responsibly.

Much of the interest around gene drive arises because they can potentially be useful to address a number of otherwise difficult to address challenges. The 3 main proposed targets of gene drives are for:

1) vectors of disease (e.g., malaria-transmitting mosquitoes);

2) invasive species causing extinctions (e.g., rodents on oceanic islands); and, perhaps,

3) agricultural pests, such as insects and weeds, though, so far as I know, much less thought and work has gone into these potential targets than the other two.

This is a very diverse group of targets, and the same genetic approach is highly unlikely to be appropriate for all of them.

Much of the concern about gene drive is because of the possibility of spread beyond the point of release (raising governance issues when borders can be crossed), but this is not a general properties of all gene drives, Instead, it is a potential property of some gene drives. In some circumstances such spread may be considered a useful property, such as making an affordable malaria control intervention in sub-Saharan Africa, which is both vast and resource-constrained. In other circumstances it would be undesirable, and one would want to have more limited spread, or no spread — so that, for example, an invasive species is controlled where it is invasive, but not in its home range, or an agricultural pest is controlled on a farmer’s field but not elsewhere. And so researchers working on these different problems will want to choose different “flavours" or types of gene drive to suit the particular problem they are tackling.

From a regulatory and policy point of view perhaps the most important consequence of this diversity of possible approaches is that any proposal to use gene drive must be considered on a case by case basis. It is already accepted that risk assessment of an LMO needs to consider the exact specifics of the modification, the organism, and the receiving environment. In the case of gene drive, there are a dozen or more types of drive that differ in their structure, mode of action, or underlying logic; the potential target species include mosquitoes, other insects, rodents, and weeds; and the potential receiving environments include rural Africa, oceanic islands, and agricultural landscapes anywhere in the world. There’s hundreds or even thousands of possible combinations here. Some might be sensible and hugely beneficial, others certainly would be dumb, and we are going to need case-by-case assessment of benefits and costs to separate them. Indeed, the need for case by case assessments has been articulated many times before, most recently by Ms Nzeduru [#9505].

Similar considerations would argue against the possibility of having detailed guidance or risk assessment procedures that cover all conceivable gene drive applications. The recent James et al. (2018, cited in #9499) recommendations focused on a much narrower scenario (low threshold gene drives in malaria-transmitting mosquitoes in sub-Saharan Africa), which seems a much more appropriate level for detailed thinking and consensus building.

Thank you very much to the moderators and contributors for a most stimulating and enlightening discussion forum to date. I work in Imperial College London trying to understand and develop the regulatory science requirements that can support SynBio applications such as gene drive in the control of the malaria vector.

I would like to comment specifically on “1.What information exists related to organisms that have been developed to contain engineered gene drives, in the light of the impacts that such organisms might have on the conservation and sustainable use of biological diversity”. I would agree with comments from Boet [9500] on gene drive and add that one of the most significant developments in this area has been from Kyrou et al 2018 (https://www.nature.com/articles/nbt.4245) , who used a CRISPR-Cas9 based approach to show, for the first-time, complete suppression of An. gambiae population in small cages without seeing signs of resistance of the targeted gene in the modified mosquito.

The authors targeted the doublesex gene which encodes two alternatively spliced transcripts, the regulation of which controls sex differentiation. The female transcript, contains an exon not found in the male transcript. CRISPR-Cas targeted disruption of this doublesex female specific transcript does not affect males, but females homozygous for the disruption show an intersex phenotype, are sterile and do not bite. A gene drive construct which disrupts this female transcript spread through caged populations of mosquitoes within 7-11 generations, reducing egg production until there was a population collapse.

Unlike previous studies, such as Hammond et al 2016 (https://www.nature.com/articles/nbt.3439) & Hammond et al 2017 (https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007039), resistance to drive was not observed in these small cage studies, presumably because the region of the doublesex gene that has been targeted is an ultra-conserved part of that gene, therefore making it less likely that it will develop mutations that could also restore the function of the doublesex gene in females. Further studies of this strain in large cages in a contained environment should determine whether any resistance to the gene drive could be observed with larger numbers in more realistic ecological conditions.

Importantly, the sequence of doublesex targeted in this study is completely conserved within the six species that form the Anopheles gambiae complex, whereas its shows divergence in more distantly related species, indicating the potential for spread of such a drive within the Anopheles complex - but not significantly beyond that. See Supplementary Figure 8 of Kryou et al 2018 (https://media.nature.com/original/nature-assets/nbt/journal/v36/n11/extref/nbt.4245-S1.pdf)

References:
Hammond AM, Kyrou K, Bruttini M, North A, Galizi R, Karlsson X, Kranjc N, Carpi FM, D'Aurizio R, Crisanti A, Nolan T. The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito. PLoS Genet. 2017 Oct 4;13(10):e1007039. doi: 10.1371/journal.pgen.1007039. eCollection 2017 Oct.

Hammond A, Galizi R, Kyrou K, Simoni A, Siniscalchi C, Katsanos D, Gribble M, Baker D, Marois E, Russell S, Burt A, Windbichler N, Crisanti A, Nolan T. A CRISPR-Cas9 gene drive system targeting female reproduction in the malaria mosquito vector Anopheles gambiae. Nat Biotechnol. 2016 Jan;34(1):78-83. doi: 10.1038/nbt.3439. Epub 2015 Dec 7.

Kyrou K, Hammond AM, Galizi R, Kranjc N, Burt A, Beaghton AK, Nolan T, Crisanti A. A CRISPR-Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes. Nat Biotechnol. 2018 Dec;36(11):1062-1066. doi: 10.1038/nbt.4245. Epub 2018 Sep 24. DOI:10.1186/s12936-018-2288-3

From Madagascar's point of view, we are aware that positive impacts can be expected from Synthetic Biology. What we oppose is the highlighting of these possible positive impacts without considering the potential negative impacts (adverse effects and environmental, social, and economic risks). We would have liked to have more information on these risks.
We emphasize that synthetic biology has impacts on communities that are working and living off the exploitation of certain natural products competing with products of synthetic biology. We therefore reiterate the inquiry we made at COP14:
Certain products derived from synthetic biology are labelled as natural products. The production of such products is less expensive than the process that leads to natural products which is expensive, hard and time consuming. This creates unfair competition. This has impact on the well-being and livelihoods of local communities who depend on these resources. These products should not be wrong labelled as natural products as they are derived from synthetic processes. This clearly defrauds customers. This fraud threatens the livelihoods of millions of indigenous people and local communities (IPLCs) around the world who are custodians of biodiversity, forcing them to abandon sustainable use practices and take up logging and poaching instead. When people's livelihoods are in danger, so is biodiversity: hence, the link with the objectives of the CBD. Furthermore, this is one of the main and urgent threats from DSI.
Biopiracy, an aspect closely related to synthetic biology and digital sequencing of information on genetic resources (DSI), has already been raised in the COP since the 2000s; results at the country level are still not being felt despite the signing and implementation of the Nagoya Protocol. We hope that the issue of biopiracy will be seriously addressed in the CBD (Forums, AHTEGs, COPs...)

Dear all,
Thanks for the discussion.

In response to [#9509]. Ms. Risa Smith noted that “The use of synthetic proteins could result in a reduction in GHG emissions from agriculture and improvements for the biodiversity that is harmed by conversion of natural systems for meat and milk production”. But we should not forget that energy is necessary for the production of synthetic proteins, for the production of which fossil fuels are still mainly used. If the meat factories of the future work on oil and coal, the long-term effects on climate can be worse than on traditional livestock farming. I think these issues require more comprehensive study.

Best regards,
Maryna Bahdanava

Dear colleagues,

I think that a broad spectrum of positive and negative effects of organisms produced with the help of synthetic biology is conceivable and some of these have been shared in this and earlier online forums. Regarding evidences to support these potential impacts, I would like to join in on Boet´s comment [#9500]. I do not know of any reliable evidence and think it would be a good start to draw on experiences with the use of LMOs since most organisms obtained with the help of synthetic biology are considered LMOs.

Since no deliberate release of organisms containing engineered gene drives has taken place, reliable data on potential positive and negative impacts is not available either. However, there have been several posts with information on the nature of different gene drives ([#9499], [#9510], [#9514] and [#9515]). Especially post [#9514] explains nicely why the potential effects will be different for each type of gene drive and why a case-by-case assessment of both the risks and benefits will be necessary.

Kind regards,
Swantje

Hello again everyone. My name is Jenna Shinen and I am a Senior Advisor contracted in the Office of Conservation and Water 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.

The United States encourages independent scientific research, development, and capacity building in many fields relevant to biotechnology and biological engineering, both domestically and with partners around the world.  Genome editing techniques, including engineered gene drives, are expected to accelerate the rate at which scientists can apply biotechnology to address medical, environmental, and agricultural challenges.  These technologies are also revolutionizing biological research, advancing our understanding of living organisms and systems, and becoming vital to powering the global economy.

As others in this forum have already mentioned, engineered gene drives have the potential to provide important benefits to conservation and human health, particularly in the areas of vector population control to help manage infectious diseases or to use new non-pesticide approaches to control pests that cause agricultural, economic, and environmental damage.  At the same time,  application of these technologies requires careful consideration by scientists and policymakers, to ensure that questions regarding safety and security are adequately addressed. Governments, academia, and the private sector should collaborate to review governance and oversight mechanisms and address potential risks associated with applications of genome editing and synthesis technologies in ways that preserve the benefits these applications are expected to provide.

Regulation and oversight of emerging technologies, like engineered gene drives, should protect safety, health, and the environment while avoiding unjustifiable barriers to innovation, stigmatization of new technologies, or creation of trade barriers.  Additionally, regulation and oversight should be based on the best available scientific evidence and be aware of the potential benefits and the potential costs of such regulation and oversight.

I look forward to the continued discussion on this topic.

Jenna

POSTED ON BEHALF OF Ms. Alda Lerayer, BIO - Biotechnology Industry Organization:
*********
I totally agree with Ms. Jennifer Shinen. This is the position Brazil supports as well.

Alda

I also agree with position of Jennifer Shinen (#9522)

Dear all,

let me contribute some publications regarding the possible impact of SynBio applications on the goals of the convention. These publication are especially relevant for assessing potentially negative impacts on biodiversity and the environment due to unintended effects, as triggered by ‘genome editing’.

To ease further discussion I group them along some categories

> There are several interesting publications showing unintended effects on the level of the genome:

Anderson, K. R., Haeussler, M., Watanabe, C., Janakiraman, V., Lund, J., Modrusan, Z., Warming, S. (2018). CRISPR off-target analysis in genetically engineered rats and mice. Nat Methods, 15(7), 512-514. doi: 10.1038/s41592-018-0011-5

Haapaniemi, E., Botla, S., Persson, J., Schmierer, B., & Taipale, J. (2018). CRISPR-Cas9 genome editing induces a p53-mediated DNA damage response. Nat Med, 24(7), 927-930. doi: 10.1038/s41591-018-0049-z

Jin, S., Zong, Y., Gao, Q., Zhu, Z., Wang, Y., Qin, P., Liang, C., Wang, D., Qiu, J., Zhang, F., Gao, C. (2019) Cytosine, but not adenine, base editors induce genome-wide off-target mutations in Rice. Science. doi: 10.1126/science.aaw7166

Kosicki, M., Tomberg, K., & Bradley, A. (2018). Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements. Nat Biotechnol, 36(8), 765-771. doi: 10.1038/nbt.4192

Zuo, E., Sun, Y., Wei, W., Yuan, T., Ying, W., Sun, H., Yang, H. (2019). Cytosine base editor generates substantial off-target single-nucleotide variants in mouse embryos. Science. doi: 10.1126/science.aav9973


> Some further publications deal with effects on the level of the epigenome:

Galonska, C., Charlton, J., Mattei, A. L., Donaghey, J., Clement, K., Gu, H., Meissner, A. (2018). Genome-wide tracking of dCas9-methyltransferase footprints. Nat Commun, 9(1), 597. doi: 10.1038/s41467-017-02708-5

Jupe, F., Rivkin, A. C., Michael, T. P., Zander, M., Motley, S. T., Sandoval, J. P., Ecker, J. R. (2019). The complex architecture and epigenomic impact of plant T-DNA insertions. PLoS Genet, 15(1), e1007819. doi: 10.1371/journal.pgen.1007819 (this publication is relevant because Agrobacterium tumefaciens is also used to insert the DNA for nucleases such as CRISPR into the genome of plants).


> There are further interesting publications showing unintended effects on the level of the genome: on the level of the cells:

Lalonde, S., Stone, O. A., Lessard, S., Lavertu, A., Desjardins, J., Beaudoin, M., Lettre, G. (2017). Frameshift indels introduced by genome editing can lead to in-frame exon skipping. PLoS One, 12(6), e0178700. doi: 10.1371/journal.pone.0178700

Mou, H., Smith, J. L., Peng, L., Yin, H., Moore, J., Zhang, X. O., Xue, W. (2017). CRISPR/Cas9-mediated genome editing induces exon skipping by alternative splicing or exon deletion. Genome Biol, 18(1), 108. doi: 10.1186/s13059-017-1237-8


hope this is helpful - maybe also for discussion under topic 3

Christoph Then

Post #9518 raises the issue of “unfair competition”. Its legal meaning can be found in Black’s Law Dictionary (https://thelawdictionary.org/unfair-competition/). “Unfair competition” seems to describe well the “passing off” of a synthetic-biology product as “natural”. However, it does not describe the labor-saving aspects of synthetic biology. Ever since the mid-19th century, economists have recognized that capital displaces labor. Displacement is a good thing as work becomes less onerous. I hasten to add that modern economists also recognize that the State should intervene and retrain the workers so displaced.

What we should seriously address is “unfair non-competition” between Users and Providers over two types of information: artificial and natural. In reductionist terms, the value that R&D adds to genetic resources is artificial information; the genetic resource itself is natural information. Unlike Users protected through monopoly patents, monopoly copyrights, monopoly trademarks and monopoly confidential information, Providers face competition, which becomes almost perfect for transboundary genetic resources. What economics predicts is what we indeed see. For example, the 2015 Brazilian ABS Legislation institutionalizes royalties as low as 0.1 percent. That number is not a typo, folks---one tenth of one percent! See: https://www.lexology.com/library/detail.aspx?g=3f8fb766-b4f0-437d-80ee-ae2ee742f360

The unfairness in treatment between artificial and natural information is so grotesque that it even lends itself to satire and song:
https://blogs.plos.org/synbio/2019/02/19/wind-blowin-in-the-brackets-tribute-to-the-convention-on-biological-diversity/

Hi All, I will combine comments from Topics 3 and 4 covering state of knowledge and potential impacts of synthetic biology applications, focusing on genome editing and LMOs engineered to contain gene drives.

1) With regards to genome editing techniques, there is accumulating evidence of unintended molecular effects, with implications for biological diversity and human health, as previously highlighted in other posts e.g. #9532.

For example, the CRISPR/Cas9 system was recently demonstrated to induce complex genetic rearrangements, translocations, small and large deletions of DNA (Kosicki et al., 2018). Such effects resulting from double-strand break (DSB) repair pathways naturally apply to other endonucleases as well as double-nickases (Alateeq et al., 2018). Reducing off-target activity will not circumvent the issues of unintended on-target effects, and challenge claims of increased safety of these newer genome editing techniques such as double-nickases. A 2019 study reported horizontal gene transfer of foreign DNA sequences in CRISPR-edited mouse cell DNA, including the incorporation bacterial DNA (derived from the laboratory procedures of amplifying CRISPR machinery) and cow DNA (derived from the foetal calf serum present in the tissue culture medium) (Ono et al., 2019). Base-editors are also being reported to induce off-target mutations in both rice (Jin et al., 2019) and mouse embryos (Zuo et al., 2019).

Unintended mutations have not been linked to in vivo pathology in mice with a new paper showing that CRISPR-induced on-target bystander mutations following DSB repair in mice induced in vivo pathology in the form of immune dysregulation (Simeonov et al., 2019).

Unintended mutations in crops or other synthetic biology products such as lab-grown meat envisaged to include genome edited processes for certain products, have the potential to pose human health risks such as altering levels of toxins, nutrients or allergens.

Other unexpected effects such as disruptions of cell cycle and DNA repair processes, suggest unique risk related factors that are unrelated to off-target DNA changes (Ihry et al., 2018; Haapaniemi et al., 2018).

Finally, such unintended effects introduce an added layer of complexity and unpredictability when genome editing techniques are employed to modify organisms in the wild, as previously raised in Topic 1. e.g. LMOs containing gene drives, viral delivery of genome editing machinery and applications like DARPAs Insect Allies project. Such effects will be difficult to predict in advance of environmental release.

2)  With regards to LMOs containing engineered gene drives, there are various knowledge gaps, risks and uncertainties relevant to potential positive and negative impacts, with implications for the three objectives of the CBD.

First I would like to agree with comments in post #9574 that there are various gene drive strategies being developed, though most of them remain in the theoretical stages. Low-threshold ‘global’ gene drives that are designed to spread throughout entire populations have however, been demonstrated in proof-of-principle experiments (though long-term efficacy with regards to resistance development is yet to be determined) and, in the case of gene drive mosquitoes, are being envisaged for release in targeted African countries. Decisions with regards to who will be the first to experience the risks and uncertainties of gene drive releases, particularly global gene drives, is a very difficult decision that warrants special consideration. There appears to be a distinction between yet-to-be gene drive systems that have increased molecular ‘checks and balances’ for increased controllability, and those that are likely to be released first.

The abovementioned unintended effects associated with genome editing tools such as CRISPR/Cas9 also have implications for gene drives. With regards to potential risks, heritable molecular off-target effects as raised by Hayes et al., (2018), could result in adverse effects e.g. altering genotype/phenotypes having knock-on effects e.g. altering toxicity to predators, altering capacity to transmit disease. Knowledge gaps remain with regards to how such effects will take effect over time and space, since gene drives modify the germline at every generation.

With regards to ecosystem risks, knowledge gaps remain with regards to potential effects of eradicating entire populations/species, making impacts very difficult to predict prior to environmental release. Further, ecological impacts may take decades to appear, making predictions and monitoring a challenge (Courtier-Orgogozo et al., 2017).  Nonetheless, population eradication has been suggested to have potentially severe ecosystem effects (Hochkirch et al., 2017). A priori analyses of ecological risks lag behind efforts to model efficacy, and is hindered by lack of base-line data on various factors relating to both target species e.g. mosquito dissemination dynamics, male population sizes, survival; and ecological aspects such as niche-replacement (also with disease-carrying vectors), effects on food web, species interactions etc, with implications for human health, biodiversity and socioeconomic effects. Outcrossing potential is much increased with gene drives, but limited data exists e.g. sequence information of potential outcrossing partners, understanding of species barriers, makes estimating outcrossing potential difficult. With regards to public health applications, modelling data is lacking on epidemiological effects. This point has been highlighted in the WHO Vector Control Advisory Group report (year) that cautions against the releases until such data are collected.

With regards to potential benefits e.g. of eradicating mosquitoes, knowledge gaps remain that should to be taken in consideration when weighing up risks versus benefits. Resistance development is a major obstacle to gene drive efficacy. Targeting conserved Anopheles species may not prevent resistance development that could occur via other mechanisms e.g. mutations in CRISPR/guide RNA sequences, gene silencing, non-molecular resistance such as sibling mating mechanisms as recently modelled by Bull et al., 2019 that raise the potential for lack of efficacy that goes beyond the control of genome engineering. Further, modelling studies to date are very limited and the most recent, and previously referenced on this forum (Eckhoff et al., 2017), rightly acknowledges limited baseline data e.g. dispersion patterns. This study also present scenarios e.g. forest fires, where populations recover. Crucially, there remains a lack of modelling that incorporates epidemiological efficacy, not just reduced population numbers of single vector species, considering there are also multiple disease vectors for malaria. Current modelling (though some further input on this would be appreciated), appears to also envisage the need for regular and numerous releases e.g. long-term weekly releases, raising uncertainties with regards to socioeconomic burden of such strategies. 

3) I would like to echo comments raised in post #9518 highlighting the potential for negative socio-economic impacts of synthetic products such as ingredients, fragrances and medicines that could threaten livelihoods. I would like to draw attention to our recent publications in collaboration with the African Centre for Biodiversity and the ETC Group on this issue and the effects on different global regions of Asia, Africa and Latin America and the Caribbean. http://www.synbiogovernance.org

4) With regards to effects of synthetic biology products such as synthetic meat, I would like to reiterate comments raised in #9520. I would like to draw attention to a new study modelling climate impacts of synthetic cultured meat presenting scenarios whereby cultured meat is not climatically superior to cattle production (Lynch & Pierrehumbert, 2019). More comprehensive life-cycle analyses are needed that incorporate the whole production system, e.g. sugar production to feed synbio microorganisms for plant-based meat alternatives (also commonly associated with adverse health and environmental impacts e.g. kidney disease epidemics and deforestation), and basal media for animal-based meat production.


Bull JJ, Remien CH, Krone SM (2018). Gene-drive-mediated extinction is thwarted by evolution of sib mating. bioRxiv preprint first posted online Feb. 22, 2019; doi: http://dx.doi.org/10.1101/558924.

Courtier-Orgogozo V, Morizot B, Boëte C (2017). Agricultural pest control with CRISPR-based gene drive: time for public debate: Should we use gene drive for pest control? EMBO Rep. 18(6):878-880

Hayes KR, Hosack GR, Dana GV, Foster SD, Ford JH, Thresher R, Ickowicz A, Peel D, Tizard M, De Barro P, Strive T, Dambacher JM (2018). Identifying and detecting potentially adverse ecological outcomes associated with the release of gene-drive modified organisms, Journal of Responsible Innovation. 5: sup1, S139-S158, DOI: 10.1080/23299460.2017.1415585

Hochkirch A, Beninde J, Fischer M, Krahener A, Lindermann C, Matenaar D, Rohde K, Wagner N, Wesch C, Wirtz S, Zink A, Lötters S, Schmitt T, Proelss A, Veith M (2018). License to Kill?—Disease Eradication Programs May Not be in Line with the Convention on Biological Diversity. Conservation Letters. 11 (1): 1-6.

Ihry RJ, Worringer KA, Salick MR, Frias E, Ho D, Theriault K, et al. (2018). p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells. Nat. Med Vol 24, 939–946. doi: 10.1038/s41591-018-0050-6

Jin et al. Cytosine, but not adenine, base editors induce genome-wide off-target mutations in rice. Science. Published online February 28, 2019. doi:10.1126/science.aaw7166. http://science.sciencemag.org/content/early/2019/02/27/science.aaw7166

Kosicki M, Tomberg K, Bradley A. Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements (2018). Nat Biotechnol. Vol 36(8):765-771

Lynch J and Pierrehumbert R (2019) Climate Impacts of Cultured Meat and Beef Cattle. Front. Sustain. Food Syst. 3:5. doi: 10.3389/fsufs.2019.00005

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


Zuo et al. Cytosine base editor generates substantial off-target single nucleotide variants in mouse embryos. Science. Published online February 28, 2019. doi:10.1126/science.aav9973. http://science.sciencemag.org/content/early/2019/02/27/science.aav9973

Dear Colleagues,

This comment will overlap to some extend with my comments on Topics 1 and 2.
Regarding the possible impacts of synthetic biology applications that are in early stages of research and development on the three objectives of the Convention I would like to highlight three current developments:

1. Increased possibilities for integration of different fields with Synthetic biology
In the last few years it was demonstrated that it was possible to design new metabolic and regulatory pathways, novel proteins and RNAs and to incorporate non-natural nucleotides into DNA and RNA and non-natural amino acids into proteins. I think it will be in near future when it will be possible to combine those technologies in a productive way. One can imagine that it will be possible to produce those non-native nucleotides and amino acids inside the cell using novel engineered synthetic pathways instead of supplying them from outside. It is likely that at least some of the enzymes that catalyse the reactions of those pathways will be designed de novo. Such organisms will open incredible new possibilities, but at the same time they can pose a huge danger for the environment and human health.

2. Development of synthetic virus like assemblies
In 2018 it was demonstrated that it is possible to design protein that is capable to encapsulate its own genome, a key characteristic of natural viruses (Evolution of a designed protein assembly encapsulating its own RNA genome, Butterfield et al., Nature 552 (7685), 415-420). At the same time was demonstrated that it is also possible to design protein molecules that specifically bind to cell receptors and activate them (De novo design of potent and selective mimics of IL-2 and IL-15, Silva et al., Nature 565 (7738), 186-191). Coupling those two developments should be feasible and will mean that it is we can develop virus like assemblies that can bind their own genomes, bind specifically to cells and get internalised. It will be relatively trivial, though technically demanding to some extend to design a genome that replicates in a specific location inside the cell and in a specific organism. Such systems can be modular, combining different receptor specificities with different genome specificities. The genomes can carry different types of cargo, for example the replication can be triggered only if specific loci are present in the genome, e.g. associated cancer in individual patient. It is hard to overestimate the potential of such systems, they can be used to target specific cell populations that carry specific mutation, and thus can be customised to target only the cancer cells in a patient without affecting the healthy ones. Such virus like reagents can be used to spread into the environment and target only specific pests or disease vectors without affecting related species. Such an approach can be even more efficient than the gene drives (both approaches can be combined). At the same time biosafety and biosecurity risks are pretty obvious.

3. New approaches for domestication
Domestication of wild plants that have not been accessible now seems to be possible within reasonable time scale (Domestication of wild tomato is accelerated by genome editing, Li et al., Nature Biotechnology 36, 1160-1163; De novo domestication of wild tomato using genome editing, Zsogon et al., Nature Biotechnology 36, 1211-1216; Rapid improvement of domestication traits in an orphan crop by genome editing, Lemmon et al., Nature Plants 4, 766-770). While we do not consider that to be synthetic biology, it may have significant consequences both positive and negative for the objectives of the Convention and its Protocols, in particular for the benefits sharing. Potential profits from newly domesticated organisms can be very significant and it will be important and may be challenging for the Parties and the developers to find mutually agreed and equitable ways to share them.

Best Regards,
Nikolay

Dear all,

I am not sure my contribution is actually relevant to the thread (maybe to question 2?), but I would anyway like to make some technical comments in response to some earlier contributions which presented concerns about finding suitable comparators for SynBio applications to assess their risks and benefits. While this is certainly true for some innovations and may sometimes require some “out of the box” thinking, I fully agree with the posts that pointed out the usefulness of experience already gained with LMOs.

The issue of unintended and off/target effects of CRISPR/Cas9 techniques was also brought up at least in #9530 and #9535. This is definitely a relevant issue when searching for proper comparators for the assessments. However, one should be very cautious in drawing conclusions from observations in one taxon to another, because the DNA damage and repair mechanisms are not fully conserved (see e.g. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617055/).

Also, while off-target issues and unintentional effects are certainly crucial in e.g. gene therapy and animal breeding, they may be less relevant in plant breeding, where subsequent selection and crossing is anyway practiced to remove unwanted effects from the cultivars. When considering suitable comparators for gene editing (although it may be debatable if gene editing actually fulfills the criteria of SynBio) I personally think it would be helpful to use knowledge already obtained from traditional mutagenesis breeding techniques. For plant mutation breeding I would like to refer to the excellent review by FAO (see http://www.fao.org/3/a-i2388e.pdf) which provides lots of useful background information on mutagenesis, including the effects on the target genome.

hello and thanks for the interesting discussion on this thread.  I am Camilla Beech an independent consultant with a long background in the regulation of biotechnology.

Post [#9483] from Maria tasks Topic 4 with several questions of which one is

Can we envisage some positive or negative impacts of the use of organisms, components and products of synthetic biology? Is there any evidence that support these impacts?
Firstly I would like to  agree with post [#9500] that we can use the existing frameworks for LMO's for synthetic biology organisms.

Secondly I would like to respond to Post [#9535]  which raises several topics with regard to the potential negative impacts of synthetic biology applications regarding LMO’s engineered to contain gene drives, such as off-target effects.  However, an off-target effect per se is not necessarily a negative impact in itself,  rather it is the consequence and the likelihood of the off-target effect being realised that should be assessed to determine the potential to cause harm.

Thirdly I would like to raise the point of contextualisation and the use of appropriate comparators regarding positive and negative impacts of the use of these organisms, and particularly organisms that are being developed for vector control purposes.

The WHO Global Technical Strategy for Malaria 2016–2030 developed a set of targets by 2030 to: reduce malaria incidence and mortality rates globally by at least 90% compared with 2015 levels; to eliminate malaria from at least 35 countries in which malaria was transmitted in 2015; and to prevent re-establishment of malaria in all countries that are malaria free. These WHO targets are designed to fulfill a target set under the United Nations Sustainable Development Goals, which was to end the epidemics of AIDS, tuberculosis, malaria, and neglected tropical diseases by 2030.

Therefore it is important to contextualise the potential impacts [positive or negative] on biological diversity with appropriate comparators, such as malaria eradication activities, which include the use of broad spectrum insecticide and habitat modification which are likely to have significant impacts on biodiversity.

Several posts from Christoph (9530, 9533) and Eva (9535) have raised unintended effects of gene editing as a matter with implications for the three objectives of the convention, as relevant to this discussion on synthetic biology. Kirsi (9538) correctly notes that it is debatable if gene editing actually fulfils the criteria of synbio, but I would go further and say I disagree with the premise that all gene editing is synthetic biology. While gene editing is one of the many tools used in synthetic biology, I do not consider that every application of gene editing results in a synthetic biology organism. As has been stated elsewhere, it is the outcome, not the tools used, that determines whether or not a particular application is synthetic biology.

I support Camilla’s point (9539) that off-target effects from gene editing do not necessarily lead to negative impacts; the outcome of off-target effects must first be considered. That the range of effects observed following double strand break repair from off-target Cas9 activity is the same as the range of effects possible through natural mutations is also relevant.

Dear moderator Maria and other Colleagues,

Thanks to Mr. Zhiwen Wang from Tianjin University for his Post [#9495]
“I am thinking that currently the organisms contain engineered gene drives should be maintained in closed system (for instance fermenter) rather than open system to protect the conservation and sustainable use of biological diversity. With the development of synthetic biology, I almost make sure we can handle this technology to make full use of its advantage and protect biological diversity as much as possible.”

I agree with this approach and would like to add some thoughts I have previously indicated in other online forum reinforcing the fact that even best labs could have an accident and we must deal with it in a responsible manner. I’m going to mention just some of them.

¨Measures based on risk assessment shall be imposed to the extent necessary to prevent adverse effects of the living modified organism on the conservation and sustainable use of biological diversity, taking also into account risks to human health…..¨ (Cartagena Protocol Art 16)

Take into account the accidental release at an early stage in the lab. Accidents happen, some of them have institutional and individual responsibilities; in addition we can face an intentional one. To avoid accidents it’s very important a Culture of Laboratory Safety, to have in place implemented the principles of biosafety such as design requirements (Secondary Containment Barriers) according to biosafety levels, Good laboratory practices and techniques, Safety equipments (Primary barriers) and a Laboratory biorisk management standard such as CWA 15793:2008 and CWA 16393 January 2012:
Application ¨The requirements of this standard are generic and are intended to be applicable to all organizations handling biological agents and/or toxins, regardless of type, size and biological agents handled. This standard takes a risk based approach but it does not employ biological agent risk classification or laboratory safety/containment levels, although such approaches can be entirely compatible with this standard. Where any requirements of this standard cannot be applied due to the nature of the organization and its processes, this can be considered for exclusion. Where exclusions are made, claims of conformity to this standard are not acceptable, unless such exclusions do not affect the organization’s ability or responsibility to control biorisk in the manner required by this standard. Any claims of exclusion shall be detailed and justification provided.
Compliance with national and local regulatory standards, regulations and requirements are of primary importance in any programme. Where any part of this standard is in conflict with any legal requirement, the conflicting part of the standard may be eligible for exemption if the legal requirement meets or exceeds the intent of this standard.¨
A biorisk management committee should be established to assist the facility director; funding and training are also relevant to minimize risk and to improve risk management.
¨Biosafety has become more politically important in recent times as well, particularly after multiple high-profile safety failures at federal and military laboratories involving smallpox, anthrax, and flu¨…. there are additional, new opportunities that will be important to pursue to increase safety in the coming years, including dedicating research funds to biosafety; expanding biosafety training into new environments, to reach the growing populations of people who are performing biological work; and leading the world to develop international biosafety norms.¨ A Biosafety Agenda to Spur Biotechnology Development and Prevent Accidents. Health Security Volume 15, Number 1, 2017
¨On 6 September, the Belgium authorities informed the European Commission, the Netherlands, ECDC and WHO about an incident that occurred on 2 September 2014. Following a human error, 45 liters of concentrated live polio virus solution were released into the environment by the pharmaceutical company, GlaxoSmithKline (GSK), in Rixensart, Belgium¨
COMMUNICABLE DISEASE THREATS REPORT Week 37, 7-13 September 2014

Kind regards,

L. Regalado

Thank you Maria for this guidance for topic #4.

This week’s discussion will focus on possible impacts of synthetic biology applications that are in early stages of research and development, on the three objectives of the Convention. Possible impacts (which could be either positive or negative) is a type of shorthand to say that we are looking at the results of a risk assessment or similar type of assessment.  It might be helpful to parse the three objectives of the Convention into a matrix with the three types of synthetic biology applications we have been talking about (organisms, components and products) so that we can compartmentalize our examples and better communicate where our concerns lie. To this end and according to my understanding, I have created the attached matrix for your consideration and have placed some examples in its cells. I hope this helps in our discussion.

I am Geoff Turner, currently working at Imperial College London, and have spent many years supporting regulatory affairs across a breadth of areas in both government and the private sector, and now the University sector, working with the Target Malaria consortium.

In response to the two part question from the moderator: Can we envisage some positive or negative impacts of the use of organisms, components and products of synthetic biology? Is there any evidence that support these impacts?

While I have expressed my position in another thread that products meeting the definition of an LMO under the Cartagena protocol should fall under guidance as such, I would like to offer a case study in which the large scale dissemination of an LMO in the environment has led to successful health outcomes.

Oral rabies vaccination (ORV) is the pre-eminent example of successful vaccination of wildlife populations which has resulted in virtual elimination of fox-mediated rabies from large parts of Western and Central Europe.

http://ec.europa.eu/food/audits-analysis/overview_reports/act_getPDF.cfm?PDF_ID=949
https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2015.4164

In summary:

A fox or raccoon dog gets vaccinated when ingesting rabies vaccine, packaged in a capsule hidden inside a tasty bait casing (together they are referred to as vaccine bait).

Vaccine baits are dropped at regular intervals from aircraft, and sometimes distributed by hand in "no-fly" areas.

30 European countries have implemented ORV programs beginning in 1978 in Switzerland and since that time around ten different attenuated rabies virus-based vaccine strains, and one recombinant vaccine were used (i.e. an LMO) 

https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0003953

Vaccine development progressed in tandem with the development of new laboratory based tools:

First generation: attenuated rabies viruses developed by conventional in vivo and/or in vitro serial passaging of virulent field virus isolates

Second generation: selection of monoclonal antibody escape mutants

Third generation: site-directed mutagenesis

Fourth generation-  recombinant vaccinia virus expressing the rabies virus glycoprotein i.e. an LMO called RABORAL V-RG

Field application of RABORAL V-RG has contributed to the elimination of wildlife rabies from three European countries (Belgium, France and Luxembourg) and in use in other parts of the world, extensively in North America

https://veterinaryresearch.biomedcentral.com/articles/10.1186/s13567-017-0459-9

RABORAL V-RG  was authorised in 1994 in Europe, prior to EC regulations requiring that Veterinary Medical Product authorisations containing GMOs must respect the criteria established in regulations on the release of GMOs in the environment (currently Directive 2001/18/EC) i.e. authorisation was  Pre- Cartagena Protocol, Pre "Synthetic Biology".

Considerations for the AHTEG and this forum are, given that: 

•The paradigm for rabies control based on oral vaccination of wild-life, using edible baits containing live vaccine distributed in the environment, was pioneered in 1978 and is ongoing, and has been successful in achieving health outcomes; and,

•The platform for delivery of the intervention remained the same over time, but the agent used to deliver immunity to wildlife (i.,e. the oral vaccine) has gone through successive technological developments employing the "biological tool-kits" available at the time, and has included the development of an LMO as one of the agents,

Was this health intervention ever synthetic biology in its history? or would it be considered Synbio if proposed now (as some may suggest)?  Would ORV only be synthetic biology in the jurisdictions that use the LMO vaccine strain?  Could it suddenly become synthetic biology if CRISPR based tools are used to modify a live viral vaccine for delivery through the existing platform?  Would aerial drone distribution rather than helicopters, coupled with a CRISPR edit, make it synthetic biology? or would an entirely synthetic viral agent to delivery wildlife immunity, make it Synbio? Just some questions to ponder and hopefully stimulate thought.

In thinking about benefits, when considering incremental technological improvements involving LMOs within a proven delivery platform such as oral wildlife vaccination, or even genetic strategies for insect sterility as an improvement to radiation based sterile insect techniques, the precedent for benefit is clear.   For proposals which offer potential step changes to delivery models such as gene-drive strategies for  vector control,  benefits can be assessed through precedents such as vector population control broadly as a recognised paradigm for disrupting disease transmission.

Thank you for the opportunity to comment

Dear Colleagues,

This has been a robust discussion and I will limit my intervention to draw attention to some recent papers that were published examining various aspects of gene drive technologies and their potential impacts on conservation as well as a new paper which examined the U.S. public's perceptions of utilizing genetic technologies for conservation purposes. In addition, I would like to again draw attention to the forthcoming report by the IUCN on synthetic biology and gene drives which will be released in the coming months.  One particular aspect of that report focuses on the indirect impacts of synthetic biology and gene drive applications which are not specifically designed for a conservation purpose.  The findings of that chapter suggest that these types of applications may have significant impacts, both positive and negative, in relation to the objectives of the Convention and should be examined as such on a case by case basis.

Campbell, K. J., Saah, J. R., Brown, P. R., Godwin, J., Gould, F., Howald, G. R., Piaggio, A., Thomas, P., Tompkins, D. M., Threadgill, D., Delborne, J., Kanavy, D. M., Kuiken, T., Packard, H., Serr, M. & Shiels, A. (2019) A potential new tool for the toolbox: Assessing gene drives for eradicating invasive rodent populations. In: Island invasives: Scaling up to meet the challenge, eds. C. R. Veitch, M. N. Clout, A. R. Martin, J. C. Russell & C. J. West, pp. 6-14. Gland, Switzerland: International Union for Conservation of Nature and Natural Resources.

Harvey-Samuel, T., Campbell, K. J., Edgington, M. & Alphey, L. (2019) Trialling gene drives to control invasive species: What, where and how? In: Island invasives: Scaling up to meet the challenge, eds. C. R. Veitch, M. N. Clout, A. R. Martin, J. C. Russell & C. J. West, pp. 618–627. Gland, Switzerland: International Union for Conservation of Nature and Natural Resources.

S. Kathleen Barnhill-Dilling * , Megan Serr , Dimitri V. Blondel and John Godwin (2019). Sustainability as a Framework for Considering Gene Drive Mice for Invasive Rodent Eradication. Sustainability. 11, 1334.

Kohl, P.A.1,2*, Brossard, D.2, Scheufele, D. A.2, & Xenos, M. A3. (2019) Public views about gene editing wildlife for conservation. Conservation Biology.

Todd Kuiken

Dear all,

I am a PhD student at UC Berkeley conducting research on the use of gene drive technology to control mosquito-borne diseases under Dr. John Marshall. While my current focus is the mathematical modelling of gene drive systems, I have previous regulatory experience through work with the U.S. Department of State and the UN Framework Convention on Climate Change.

In the interest of both adding to the review of the current state of knowledge (Topic 3) and sharing new applications of organisms developed to contain engineered gene drives along with their impacts on the three objectives of the Convention (Topic 4), I write in support of the statements made by participants [#9514], [#9503], and [#9499]. Further to the points made by these participants, I include here information on a paper that reports the creation of a gene drive system in the major agricultural pest Drosophila suzukii.

[Paper: Buchman A, Marshall JM, Ostrovski D, Yang T, Akbari OS. (2018). Synthetically engineered Medea gene drive system in the worldwide crop pest Drosophila suzukii. Proceedings of the National Academy of Sciences, 115 (18), pp. 4725-4730.] 

The paper outlines the use of the synthetic Medea gene drive system in a crop pest common to soft-skinned fruits. An invasive species originating in Japan and now found on every continent except Antarctica, D. suzukii lays its eggs inside ripening fruits, resulting in significant losses to farmers. Experimental results implementing this gene drive system in the lab suggest that it could be maintained at high frequencies in a wild population and potentially spread to local fixation with specific adjustments.

Future development of this system carries implications for the first and second objectives of the Convention, but the impacts are beneficial given the severe negative effect of invasive D. suzukii on food production and security worldwide. The potential benefits offered by this genetic innovation thus stand to serve all those affected by this agricultural pest.

Regards,

Valeri Vasquez

Dear Maria and colleagues,

From my point of view, if you develop products with genetic resources and derivatives through synthetic biology, you could directly impact the scope of the third objective of the Convention on Biological Diversity, in relation to the fair and equitable distribution of the benefits derived from the use of biodiversity, since this objective will not have a basis, since an equitable distribution of benefits would not be necessary because production by means of synthetic biology does not consider considering the origin of the resources and the benefits would be exclusive of the person who performs the production synthetic

It is important to bear in mind that for those countries that are part of the Nagoya Protocol, synthetic biology would affect the development of the objectives of said protocol, taking into account that the derivatives on which access to genetic resources is determined could be replaced. for products of synthetic biology and access permits or mutual agreements would not be required to access any type of associated resource (CBD, 2015).

Dear participants on the online forum,

The interventions on this topic have been very interesting.  The information shared here will be very useful to inform an initial scoping of possible
harms that could be attributed to products of synthetic biology, as part of risk assessments that
will be done on most of these products under the Cartagena Protocol.  As the December 2017
report by the AHTEG on Synthetic Biology has concluded,“...most  living  organisms  already developed or  currently  under  research  and  development  through  techniques  of  synthetic  biology, including  organisms  containing  engineered  gene  drives,  f[a]ll  under  the  definition  of LMOs as  per  the Cartagena Protocol."  We should be cautious that the information provided in
this forum regarding the potential impacts, both positive and negative, is not evidence that any of
these impacts will be realized.  That evidence will only be obtained through sound, science-based,
case-by-case assessments, following the principles (at least as far as risks are concerned) laid out
by the Cartagena Protocol.  Furthermore, the information provided here does not indicate that the
possible impacts of products of synthetic biology (recognizing that the term is still
vague in our ongoing discussions), including organisms that contain
engineered gene drives, are unique and have not been considered before with regard to other LMOs. While it is yet to be determined which LMOs are products of
synthetic biology (including whether LMOs containing engineered gene drives are indeed to be
included in this classification), risk assessment of these LMOs can be conducted under the Cartagena
Protocol, supported by experience with risk assessments done on non-LMOs with similar
characteristics, such as biocontrol agents. This opinion is consistent with similar views expressed by experienced risk assessors such as Boet Glandorf (#9500), and Louisa Matthew (#9529).

Dear Maria, Dear all
There are few ideas that I would like to highlight:

- In the absence of appropriate mechanisms for benefit sharing with the custodians of the natural resources and their associated traditional knowledge, Biosynthetic routes aiming to commercially replace natural sources would have devastating socio-economic impacts, especially with regard to the value of biodiversity to indigenous peoples and local communities. We already noticed how the market price of natural product get affected when companies just declare working on semisynthetic analogues like the case of artemisinin

- Synthetic biology applications are in early stages of research and development. Sometimes the produced synbio organism do not perform as expected in the wild. E.g. Gene drives get thwarted by emergence of resistant organisms. Having said that, claimed positive impacts need to be checked that they are factious and not just hopes.

- As is the case with any other new technologies that are to be released in the environment some of the negative effects are hard to predict given the lack of sufficient information and the complex interactions in the ecosystems.

- A good gene drive system is designed to spread and remain. Using such technology to wipe out a species could have irreversible and uncontainable effects.

- Sometimes existing risk assessment methodologies are not fit for purpose when it comes to synbio  especially that we are dealing with parts and products also.

Best regards,
Prof. Dr. O.A.El-Kawy

Dear moderator and online forum colleagues,
Greetings from Malaysia, I am Kok Gan Chan, FASc, PhD, from Malaysia.

Thank you Maria for being the moderator, and am glad to see many interesting posts on Topic 4: “Possible impacts of synthetic biology applications that are in early stages of research and development on the three objectives of the Convention”.

As post by Maria [#9483], as Synthetic Biology is capable to “synthesize” novel GMO with novel traits that may enable the said SynBio GMO to thrive and excel in a given environment. In the spirit of the Precautionary Principle in the Convention, this impact should be assessed in a long term basis. I personally do not see any report on this kind of studies as Maria has pointed out, the concern may be more on the conservation and sustainable use of biological diversity as SynBio GMO may have traits that will be too novel that may not have been seen before. On this point, I share the same view with Wei [#9487].  As I personally feel that conclusive evidence on this may be lacking, and as the previous AHTEG member on Risk Assessment, therefore Precautionary Principle again, is useful in this issue.


Thank you and I wish everyone a nice weekend.

Best regards,
Kok Gan Chan

Dear Maria, thank you very much for moderating this forum. Thank to all participants for interesting discussion.
Synbio organisms can have both positive and negative impacts depending on the new features produced in them. Positive effects clearly visible to those being developed to treat diseases. There are many articles on this subject and discussions in this forum, so I will not repeat.
As for negative impact it is very well described by Helmut Gaugitsch in topic 3 post [#9540] for engineered gene drives. Organisms derived by gene drives or organisms that would be derived by other techniques and possess the potential to alter non-target populations, may lead to ecosystem change or succession. It is not always possible to predict what will be in the long term. Even if the preliminary modelling have been developed.
As for organisms that are intended for contained use (at early stage of development and that have not yet passed the risk assessment and got the approval, pathogenic or conditionally pathogenic organisms) in the post [#9542] it was very well noted what can happened if organisms that are not intended for release into the environment will escape from contained system. Unfortunately not always strict measures of prevention from contact with environment that should be followed are implemented, there may be a human factor or an accident, for example. In this case we need to take care about monitoring techniques that should be developed at the very beginning of such organisms development. Not only appropriate risk assessment guidance should be developed for such organisms, but it is necessary to carefully design clear guidelines for monitoring.
Best wishes and good weekend,
Galina

Dear colleagues,

To answer the question
- Can we envisage some positive or negative impacts of the use of organisms, components and products of synthetic biology? Is there any evidence that support these impacts?

I posted some thoughts in the topic 3 discussion which is highly related to this question (#9560). As I said, high accurate tools for computer modelling of the biodiversity dynamics and impact predictions is still to be developed. I am sure that these ambitious goals should be assigned to the scientific society because without these implements we will only be doomed to find out unexpected delayed effects of SynBio products "ex post".

Sincerely,
Nina Voronova

The Chairs questions about Topic 4 asks for evidences that supports impacts – positive or negative - of synthetic biology in early stages of research and development.

From a regulatory perspective, positive and/or negative impacts of synthetic biology to biodiversity, in reality, would only be accessed with research, development and the adoption of risk assessment and management, that are at the core the precautionary approach that fundaments several CBD Decisions. With no scientific development, no sound evidences would be achieved aimed at driving effective measures to avoid and/or minimize possible impacts.

Possible or tangible impacts to biodiversity should lead the search for answers, assuming that the three objectives of the Convention are narrowed to this aim. With no concrete impact to the conservation and sustainable use of biodiversity, comprising the access to genetic resources, traditional knowledge and benefit sharing, there is no space for discussing damages at the CBD.

The socio and economic debates around synthetic biology, as well as the broader socio and economic concerns at the Cartagena Protocol Article 26, must be framed by measurable and concrete impacts to biodiversity. This should be the trigger that would possibly lead to socio and economic impacts arising from these previous damages. Otherwise, any socio and economic argument could imply biodiversity damages, what, in essence, would need to be critically based on sound indicators.

Technologies that are in early stages of research and development needs to be carefully assessed following risk assessment approaches and experiences, considering countries regulations and international protocols towards this.

Gene drive applications, for instance, opens and enormous debate regarding possible damages to biodiversity. Like the case of traditional LMOs, risk assessment approaches should consider the specificities of the modifications, the organism and foreseeable outcomes into the environment. Without risk assessment and management it is not feasible to answer the challenging questions related to the new technologies.

Several messages relates to the connections of digital sequence information (DSI) and synthetic biology. It seems essential to see DSI as a broad and promising source of data to that could lead to biodiversity comprehension, understanding and conservation. The ways DSI will evolve from a technological and a regulatory perspective, at the CBD and at Parties regulations, should not imply damages to biodiversity per se.

In this sense, the possible connection of synthetic biology being developed with the use of digital sequences should not be understood as damages to the CBD objectives. The fact that Parties are discussing how to manage and to regulate DSI, and the several unanswered questions up to now, does not allow proper conclusions in this regard.

Dear all,

Regarding CRISPR-Cas9 tools are promising, “an indispensable tool in biological research” and still in development as a need to overcome the concerns and to improve the technique in order to obtain better results, the reengineering and the evolution of a second generation of genome editing tool are part of the efforts. It means for my point of view a great advance, in some extend not yet mature and one more reason to a precautionary approach and additional measures to avoid negative impacts on the conservation and sustainable use of biodiversity and the human health as well. In some of my previous posts there are also information relevant to this issue
Positive results are encouraging and at the same time need enough time to be validated, have appropriate comparators and take into account the effects at the ecosystem level, mainly when there is the intention for an environmental release.

“Re-engineering CRISPR-Cas9 tools

Exploring different CRISPR systems requires extensive understanding and characterization of new Cas proteins. Thus, in parallel to these studies, there are increasing efforts to re-engineer the already well characterized Cas9 proteins. This research direction is focusing on achieving three major goals:
(i) reducing the size of Cas9 nucleases,
(ii) increasing their fidelity, and
(iii) expanding the targeting scope of Cas9 variants. Although there has been a limited advance in reducing the size of existing Cas9 proteins, several groups have altered the Cas9 PAM requirements and targeting specificity”

 Repair of double-strand breaks induced by CRISPR–Cas9 leads to large deletions and complex rearrangements

“The utility of the CRISPR–Cas9 system for gene therapy in humans has been recognized and extensively investigated. Initial concerns about the off-target activity have been addressed by the development of sensitive detection methods, as well as modified Cas9 enzymes and improved delivery protocols that limit this type of damage
Studies using paired gRNAs to induce localized deletions also reported generation of more complex genotypes, such as inversions, endogenous and exogenous DNA insertions, and larger than- expected deletions
Furthermore, lesions distal to the cut site and crossover events were identified. The observed genomic damage in mitotically active cells caused by CRISPR–Cas9 editing may have pathogenic consequences.”

“Evolution of second-generation CRISPR gene-editing tools

….these so-called second-generation genome-editing tools are able to precisely convert a single base into another without causing DNA DSBs” (double-strand break at a target site)


nature biotechnology advance published online 16 July 2018

http://dx.doi.org/10.1038/nbt.4192

I wish all a nice weekend

Kind regards,

L. Regalado

I’d like thank the moderator, Maria, and the participants for this interesting discussion. 
Topic 4 asks for evidence or information that supports potential positive or negative impacts of synthetic biology in the early stages of research and development.
Synthetic biology offers the possibility of producing a very wide-range of organisms, components and products. It can produce smart prosthetic skin or textiles; a variety of LMOs, pharmaceuticals, chemicals; etc. While we can envisage some positive or negative impacts of the use of organisms, components and products of synthetic biology. Coming with evidence to support them is another story. As most of the potential applications are still on research, it is neither always clear whether the aspirations will become real nor possible to provide direct evidence of either positive or negative impacts. The set of potential benefits and adverse effects will depend on a case-by-case basis, what it is, how it’s and where it’s used, how they compare to existing alternatives, the challenges faced, etc.
As pointed out by Boet’s comment [#9500] and others, we can draw on experiences with LMOs, biological control. As well as, with the experience with other related or comparable products/applications. In addition, it is important to remember that before becoming available, those products, applications… are subject to a case-specific set of risk assessment and management and regulations. In addition, it is important to keep in mind as mentioned by Jenna [#9522] that these technologies are also advancing our understanding of living organisms and systems and are becoming vital to powering the global economy. In addition, we need to foster research to find solutions to the existing and emerging challenges we face.

bon weekend, Lúcia

Thank you to our moderators and all for the informative discussions on this topic.

1) I’d like to add to the point raised by posts #9542 and #9559 on the risks of accidental escape from the laboratory. The risk of accidental or unintentional release into the environment, either through laboratory accidents or human mistakes, always remains, with ensuing potential impacts.

The novel capabilities of synthetic biology, gene drives in particular (due to their proliferative design), and their potentially increased impacts on biodiversity merit a serious assessment of risks stemming from contained use. A series of recent incidents at high containment laboratories, including repeated accidental releases by laboratories regarded as being highly professional and secure, draw attention to the inevitability of containment failure. Recent examples include accidental distribution of potentially pandemic influenza viruses by the US Centers for Disease Control and Prevention (CDC, 2014a), the discovery of improperly stored and forgotten samples of viable smallpox virus at the US National Institutes of Health (CDC, 2014b; Christensen, 2014), and numerous incidents of accidental distribution of viable anthrax bacteria by the US Army’s Dugway Proving Ground (Chappell, 2015).

For LMOs containing engineered gene drives especially, the consequences are potentially great, because even a small unintentional release, particularly of a ‘global’ gene drive, may well result in an extensive spread of the gene drive (Esvelt and Gemmell, 2017; Noble et al., 2017; Simon et al., 2018), possibly throughout an entire species.

Other applications described as contained use, for example, large-scale biofuels production, can involve cultures of tens of thousands of liters of organisms and carry greater risks than envisaged.

2) With regard to potential socioeconomic and cultural impacts, I agree with posts #9518 and #9540.

The use of synthetic biology to engineer microbes that can excrete compounds that mimic valuable substances, such as those found in vanilla, stevia, shea butter and silk, etc., will threaten the market for natural products and adversely affect the livelihoods of farmers and indigenous peoples who cultivate or harvest the products, as well as have impacts on the objectives of the Convention, in particular on conservation and sustainable use of biological diversity.

Furthermore, proposals on LMOs containing engineered gene drives have been envisaged for places such as Hawaii, New Zealand, Australia and West Africa, which include areas that indigenous peoples have traditionally owned, occupied or otherwise used or acquired. There could be impacts, for example, a gene drive may cause a biological resource that is used by indigenous peoples to become extinct or to not perform as expected, or the modification could cause the resource to be of lower value to the indigenous peoples. The general rights of indigenous peoples over their land or territories and resources are recognised in the UN Declaration on the Rights of Indigenous Peoples and include that of their productive capacity (Article 29), and to genetic resources and seeds (Article 31).

It is thus important to obtain the free, prior and informed consent of potentially affected indigenous peoples and local communities, as established by the UN Declaration on the Rights of Indigenous Peoples. This was reiterated at COP 14 as a condition that has to be met before any introduction into the environment of LMOs containing engineered gene drives, including for experimental or research and development purposes (Decision 14/19).

References:

Centers for Disease Control and Prevention (CDC) (2014a). Summary of the Inadvertent Shipment of an Influenza Virus H5N-containing Laboratory Specimen, 11 July 2014. https://www.cdc.gov/flu/news/h5n1-influenza-shipment.htm

Centers for Disease Control and Prevention (CDC) (2014b). CDC Media Statement on Newly Discovered Smallpox Specimens, 8 July 2014. https://www.cdc.gov/media/releases/2014/s0708-nih.html

Chappell, B. (2015). Live Anthrax Was Mistakenly Sent To 9 States And A U.S. Military Base.  NPR 28 May 2015. https://www.npr.org/sections/thetwo-way/2015/05/28/410220914/live-anthrax-was-mistakenly-sent-to-9-states-and-a-u-s-military-base

Christensen, J. (2014). CDC: Smallpox found in NIH storage room is alive. CNN 11 July 2014. https://edition.cnn.com/2014/07/11/health/smallpox-found-nih-alive/index.html

Esvelt, K.M. and Gemmell, N.J. (2017). Conservation demands safe gene drive. PLoS Biol
15(11): e2003850. https://doi.org/10.1371/journal.pbio.2003850

Noble, C., Adlam, B., Church, G.M., Esvelt, K.M. and Nowak, M.A. (2017). Current CRISPR gene drive systems are likely to be highly invasive in wild populations. bioRxiv, November 16, 2017. doi: https://doi.org/10.1101/219022

Simon, S., Otto, M. and Engelhard, M. (2018). Synthetic gene drive: between continuity and novelty. EMBO Reports e45760, DOI 10.15252/embr.201845760

United Nations Declaration on the Rights of Indigenous Peoples (2008). https://www.un.org/esa/socdev/unpfii/documents/DRIPS_en.pdf

Dear Maria and Colleagues,

My name is Chalinee Kongsawat and I work for National Science and Technology Development Agency, Thailand.

I agree with the posts of Boet (#9500), Louisa (#9529) and others that there is no clear exiting information of the impacts on the conservation and sustainable use of biological diversity from organisms containing engineered gene drives. The risk assessments on a case-by-case basis are very important to evaluate the potential impacts of organisms containing engineered gene drives.

Best regards,
Chalinee

Dear all—

Bob Friedman again, with the J. Craig Venter Institute.  As we know, this Topic 4 asks us to identify possible impacts of synthetic biology applications that are in early stages of research and development on the three objectives of the Convention.  Our moderator Maria asks us to consider both positive and negative impacts.  I agree with many of the participants who have observed that impacts from these early-stage applications can only be assessed on a case-by-case basis, considering the specifics of each anticipated application, (for example, [#9499], [#9500], [#9514], [#9546], [#9554], [#9566] and others).

While some proposed applications might be just silly or worse, I do think it is important that we keep in mind that the vast majority of synthetic biology applications intended for use in the environment are intended to enhance the conservation and/or sustainable use of biodiversity and to help achieve Sustainable Development Goals. Several participants have pointed out that a soon-to-be-released IUCN report examines many such proposed applications.  I would like to share two reports available today that review and identify such early-stage synthetic biology applications intended to help solve current, significant sustainability challenges.

Piaggio et al., 2017, “Is it time for synthetic biology conservation” (Trends in Ecology & Evolution, February 2017, Vol. 32, No. 2) reviews a long list of conservation problems with possible solution through the application of synthetic biology, including invasive species, pathogens, habitat conservation, loss of biodiversity, overexploitation, and pollution (attached below).  Lorenzo et al., “The power of synthetic biology for bioproduction, remediation, and pollution control” (EMBO reports e45658 | 2018) review early-stage synthetic biology applications intended to help society achieve the Sustainable Development Goals (attached below). 

Again, each such application, once further developed, must be examined on a case-by-case basis to assess how well it might achieve its intended goal (i.e., to help solve an already significant sustainability challenge), as well as to anticipate unintended, negative consequences.  In practice, this is a sequential and iterative process:  throughout the research and development process, potential positive and negative impacts are evaluated and weighed, and compared to possible alternatives.  One of the defining characteristics of synthetic biology is that it follows a cycle of “design, build, test, learn, and repeat”.  Most early-stage ideas never make it out of the laboratory.  Of those that do, some will either fail or be altered as a result of regulatory review.  But given the magnitude of the sustainability challenges already faced by society, we cannot afford to lightly dismiss opportunities for solutions.

Regards,
Bob Friedman

Dear Colleagues

I support Camilla’s point (#9539) that “it is important to contextualise the potential impacts [positive or negative] on biological diversity with appropriate comparators, such as malaria eradication activities, which include the use of broad-spectrum insecticide and habitat modification which are likely to have significant impacts on biodiversity”.

Kind regards, Dan Tompkins.

Dear Colleagues

Responding to the comment by Ms. Li Ching Lim [#9567] that “proposals on LMOs containing engineered gene drives have been envisaged for places such as Hawaii, New Zealand, Australia and West Africa”, please note that the authorities responsible for conservation in New Zealand have envisaged no such thing.

As many are aware, New Zealand biodiversity faces serious invasive species issues. All developments that could potentially assist with these issues are being assessed, including potential synthetic biology solutions. However, application of any such solution is not envisaged at this time, given that all current proposals are theoretical only, let alone have had both (i) appropriate risk assessment carried out, and (ii) appropriate social and policy discussion and support.

Any statements to the contrary are academic positioning and/or media speculation.

Kind regards, Dan Tompkins.

Comment #9518 from the colleague participant from Madagascar points out relevant aspects of the possible impacts of SynBio in the “early stages of research and development on the three objectives of the Convention”.

First of all, the idea that we are in the early stages of research and development of Synthetic Biology, is from my point of view, a very subjective idea. A remarkable characteristic of this new techno scientific discipline -Synthetic Biology- is the velocity from which the discoveries and applications of Synbio spins off to societies via Biotech companies, new products, etc.  I assume we all are aware that many companies have already invested a lot of funds in order to develop new processes and products from Synthetic Biology, some goods such as vanillin, stevia, patchouli, sandalwood, among others, are target of Synthetic Biology companies. These products are low volume but high value, due in part to the bio-cultural context in which these are produced. Additionally, the production of these goods is a very important part of the local economies. In this context, the virtual (or actual) products of Synthetic Biology, the prospection and speculation for business and the national and international regulations, may consider the implications of the eventual substitution or competition of Synbio goods and products with conventional/traditional products.

All these considerations apart from the comments and links to scientific evidence posted by fellow participants indicating the huge gaps of knowledge on the possible outcomes of this technology at the ecological and biodiversity levels, off-target effects of Synbio applications (i.e Genomic edition through CRISPR-Cas9 in certain models) and very recent documents that exemplifies regulation processes that overlooked examination (even case by case) and ended approving products which lack a more detailed assessment.

Regards,

Emmanuel González-Ortega

Dear colleagues,
First of all I would like to thank Maria to guide us thought this important discussion.

I would like to mainly cross reference to some of my thoughts in discussion 1 and 3 that might be important in this context as well:

- GM-Virus applications in agriculture including those that are transmitted by insects (HEGAAs)
- Re-domestication of crop plants
- Xenobiological developments
- GM applications in the nature conservation sector

Especially in the last example it is important to bear in mind that genetic alteration of wildlife brings along some basic questions on our concepts of nature conservation and have by this impact on the goals of the convention. We therefore need a technology assessment approach in this context, that takes into account aspects that go beyond a mere risk assessment.

In addition, I would like to comment on the relation of genome editing and synthetic biology. I my opinion genome editing is a tool, that can be applied in synthetic biology (just like other tools like for example PCR). It is therefore used in synthetic biology. However not all synthetic biology applications make use of this tool.

All the best
Margret

Dear all,
I would like to support Dan Tompkins' post #9575 regarding the fact that applications of LMOs containing gene drive have not yet been made in New Zealand, and to add that those have not yet been made in West Africa or any other part of Africa either (and to my knowledge not in Hawaii either). There is a confusion between applications being developed to address particular challenges - such as malaria in Africa - and regulatory applications being made in those countries.
LMOs containing gene drive mechanisms are still under development as mentioned by several posts. This work is taking place in containment and appropriate safeguards in place (Akbari et al, 2015), which addresses some of the concerns raised by post #9567.
As highlighted by Dan, before any such application to release can be made, appropriate risk assessment would be required as well as appropriate social and political support. As highlighted by post #9539 and #9574, decision-making on the opportunity to release an LMO containing gene drive mechanism would need to be contextualise with the alternatives (e.g. large-scale use of insecticides and habitat modification in the case of malaria, large scale use of rodenticides for invasive species on islands). The IUCN report that will be published soon, highlights the necessity to assess those alternatives when considering synthetic biology.
Socio-economic considerations have been raised by a number of posts (#9567, #9518, #9540). Those considerations as well as public health considerations need to be carefully evaluated. Those considerations could be negative or positive impacts. A separate work stream of the CBD is in place to propose further guidance on how such assessment should be carried-out. However there are precedents from which this sector can learn from  (such as the performance standard 1 of the International Finance Corporation).
Warm regards
Delphine

Dear all,

I am Fred Gould, Co-Director of the Genetic Engineering and Society Center at North Carolina State University in the USA. I have done theoretical and ecological work with diverse gene drive systems for over 18 years.

I have seen a number of posts continue to refer to gene drives with the assumption that if a small number of individuals are released, or escape from a laboratory they could spread throughout a species range. This may be theoretically possible for a specific type of gene drive, but we need to be careful with the term gene drive, because such spreading would not be possible for some types of gene drive.

I think it is worth quoting from comments of Austin Burt [#9514] that....
" For me it is important to understand that gene drive is not a single thing, but more of an umbrella term under which there are many possibilities. There are low threshold drives, high threshold drives, integral drives, split drives, daisy drives, daisy field drives, tethered drives, and sex-limited drives, and the list continues to grow. Many of these use much the same molecular tools (e.g., CRISPR/Cas9 nucleases), but the arrangement or configuration of these tools differs, which means they would behave differently in a population."

Gene drives are being developed that are engineered to spread within local populations when the engineering individuals are released in high numbers relative to the natural population (Akbari et al. 2013, Reeves et al. 2014, Buchman et al. 2018, Oberhofer et al. 2019), but there is no expectation that they could spread to other populations without substantial human assistance for further large releases.

The risk assessments for spatially and/or temporally limited drives should be different than for low/no threshold drives that have no spatial or temporal limits.

I suggest that whenever the term gene drive is used in our discussion it should be modified to indicate whether it is or is not a spatially and temporally unrestricted gene drive.


Akbari OS, et al. (2013) A synthetic gene drive system for local, reversible
modification and suppression of insect populations. Current Biol. 23:671–677.

Buchman AB, Ivy T, Marshall JM, Akbari OS, Hay BA. 2018. Engineered reciprocal chromosome translocations drive high threshold, reversible population replacement in Drosophila. ACS Synth. Biol. 7:1359-1370.

Oberhofer G, Ivy T, Hay BA (2019) Cleave and Rescue, a novel selfish genetic element and general strategy for gene drive. Proc Natl Acad Sci USA, 10.1073/pnas.1816928116.

Reeves RG, Bryk J, Altrock PM, Denton JA, Reed FA. 2014. First steps towards underdominant genetic transformation of insect populations. PLoS ONE, 9, e97557.

Dear Maria and fellow participants,
I am a PhD researcher based at the University of Bristol, UK. My research has been looking at direct and indirect socioeconomic impacts (both positive and negative) of synthetic biology commodity replacements, and how these impacts relate to biodiversity goals among other factors. While I am in the final process of compiling my data and thesis, I am able to report early findings pointing to correlations with the disincentive to plant crops that are in the process of being biosynthesised. My fieldwork has focused on the global economy of stevia, especially in its centre of origin in Paraguay. Stevia is one of the few remaining cash crops suitable for small farmers (less than 10ha) in Paraguay to cultivate within diverse agro-ecosystems (of subsistence farming and small-scale commercial farming) (Oxfam 2018). Without a reliable cash crop many farmers are having to sell land. In Paraguay land is often sold into extensive soy plantations and cattle ranches with devastating effects on biodiversity (Ortega et al 2017). Many businesses, farmers and processors interviewed in Paraguay stand ready to invest in small farms and increase stevia production if demand returned. However, over the last ~3 years demand has steadily decreased in Paraguay, while demand globally for steviol glycosides has increased. It is difficult at this stage to pinpoint biosynthetic steviol glycosides as the fundamental cause, as there are multiple market shifts that are affecting global supply and demand. It should be noted that in interviews with those in the stevia business sector, biosynthetic production is thought to be a factor. I hope to provide more insights into biosynthesis commodity substitution as my research progresses over the following year. The challenges of how to govern this emerging area remain complex but certainly worth further deliberation and horizon-scanning within the CBD.
With best regards,
Molly Bond
References:
Oxfam Intermon (2018) Evaluación final del Proyecto “Incorporación de la agricultura familiar al mercado de la Stevia en Paraguay” Available at: https://www.oxfamintermon.org/es/documentos/19/11/18/evaluacion-final-paraguay-octubre-2017-laboratorio-vinas
Ortega, G., Gervasio Apipé, Claudia Ávila, Ana Portillo, Joyve Vázquez, Silvana Lezcano, Quintín Riquelme, Verónica Serafini Geoghegan, Abel Irala, Alan Fretez Bobadilla, Mirta Barreto, Elizabeth Bravo, Abel Areco, Luis A. Caputo, Lea Schatzman, Sofía Espíndola, Luis Caputo, Víctor H. Imas, Carlos Vicente, Pablo Angulo, Estela Benítez Leite, Susana Barreto, Roger Monte Domecq, Nora Neris, Hebe González & Marielle Palau (2017) CON LA SOJA AL CUELLO 2017: Informe sobre agronegocios en Paraguay. ISBN:  9789000073245 Available at: https://www.scribd.com/document/384603532/Con-La-Soja-Al-Cuello-Marielle-Palau-Ano-2017-Portalguarani

Posts #9567,#9579, #9535, #9555, #9564, #9567, #9579 and #9582 cite socio-economic considerations. To grapple with the leading consideration, viz., benefit sharing, requires a modality for the “Global Multilateral Benefit-sharing Mechanism”, which is Article 10 of the Nagoya Protocol. Proposed legal elements have been published in the Appendix to the open-access Spanish translation of “Genetic Resources as Natural Information: Implications for the Convention on Biological Diversity and Nagoya Protocol” (Routledge, 2015, Spanish translation 2018, pp. 121-128, https://spda.org.pe/?wpfb_dl=4131 ).

For the English and French (forthcoming) versions of the Appendix, see the intralinks to:
https://uni-giessen.academia.edu/KlausAngerer/Drafts

English: “Proposal: Legal Elements for the ‘Global Multilateral Benefit-sharing Mechanism’ as contemplated in the Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilization”

Spanish: “Propuesta de elementos legales para un ‘Mecanismo Mundial Multilateral de Participación en los Beneficios’ tal como se contempla en el Artículo 10 del Protocolo e Nagoya sobre Acceso a los Recurso Genéticos y Participación Justa y Equitativa en los Beneficios que se derivan de su utilización”.

Dear Forum Participants,

Thank you very much for your commitment during this week to highlight relevant aspects that we should keep in mind when considering the possible impacts of SynBio in the early stages of research and development on the three objectives of the Convention. 
The information shared shows us that many of the developments and applications of Synthetic Biology are indeed in early stages of implementation and that many of them are performed under contained conditions. There is still a lack of experience in the analysis of possible impacts of the release of SynBio products into the environment.
As posted by #9575 and supported by others, when talking about the release of organisms, components and products of synthetic biology into the environment, it should be imperative to previously carry out: (i) appropriate risk assessment, and (ii) appropriate social and policy discussion and support.

Thank you again for your insightful contributions. The report of Topic 4 will carefully try to reflect all your points of view related directly to the subject we have been discussing during these days.

Kind Regards,

Maria

Dear All – Thank you once again for the opportunity to make inputs into this discussion.
I would essentially like to concur with others #9570, #9554, 9500, #9594 but also emphasise that every technology is developed because of its potential benefit to society and/or the environment.  Whether or not a technological application is exploited depends on a lot of things e.g. efficacy, regulation, demand etc. #9522, #9566. So, I think we ought to be cautious and refrain from making blanket statements on the potential impact (positive or negative) of a whole suite of tools when in fact in a coherent system such assessments are made case-by-case per product.

Regards

Kelebohhile

Dear All,

I join other colleagues in thanking Casper and Maria for agreeing to moderate the discussions on the Topics 3 and 4.

This post is submitted under both Topic 3 and Topic 4, because the topics are closely related, which is also illustrated by the fact colleagues submitted thoughts on the heading of Top4 under Topic 3 and vice versa.

My contribution:

General.
The exchanges under Topics 3 and 4 show again how challenging it is to discuss SynBio without a good description of what SynBio is, or at least what the key characteristics of SynBio are. As a result, there are very different perceptions of what falls under the heading of SynBio. As Marcelo Henrique Aguiar de Freitas [#9503] said, Synbio is a natural evolution of the technologies and techniques that is used to overcome challenges, and as Jing Xu [#9493] said: Synthetic biology is a combination of many technologies. I also agree with those who commented that while SynBio can include the use of genome editing, not every application of genome editing results in SynBio. Likewise, not every application of genome editing results by definition in an LMO.
For a meaningful debate on status of developments, anticipated benefits and potential risks it is also essential that we keep making important distinctions, such as between contained applications and releases (see for example Louisa Matthew [#9513]), between plants, animals and micro-organisms, status of development. With regard to gene drives, Austin Burt [#9514] makes the important point that many of these strategies have not yet even been demonstrated in the lab, but instead have only been demonstrated in computer simulations.

Current state of play.
While in relation to Synbio often reference is made to high pace developments, I believe that Nikolay Tzvetkov [#9534] makes a good point that the current state of knowledge on potential positive and negative impacts of SynBio will to a large extent be the same as in 2017.
Yet, in terms of ‘horizon scanning’, Nina Voronova [#9560] makes a good point that given that pesticide usage for pest management is restricted in many European countries, the focus is again on developing new biological agents for pest control and, since the attempts made in the last century were not as successful as we had hoped, the new agents must be genetically modified and released into open areas to work.

Anticipated benefits.
As the submissions of Marcelo Henrique Aguiar de Freitas [#9503], Jing Xu [#9493], Luz Stella Barrero [#9501], Risa Smith [#9509], Felicity Keiper [#9572], Chinyere Nzeduru [#9505] and others illustrate, the anticipated benefits of the application of SynBio are many and very diverse.

Potential risks, regulation and risk assessment.
As Taye Birhanu [#9531] and others have said, the current and foreseeable applications of SynBio involve the use of LMOs, i.e. the case by case AIA procedure for import of SynBio organisms applies, as well as other procedures of the Cartagena Protocol.
For those cases, the risk assessment as laid down in Annex II of the Cartagena Protocol is applicable and can be applied. These risk assessments are conducted on a case by case basis, looking at the characteristic of the host, the inserted or modified traits and the receiving environment. With regard to gene drives, Austin Burt [#9514], Delphine Thizy [#9499] and Fred Gould [#9581] rightly underlined that gene drive is not a single thing, but more of an umbrella term under which there are many possibilities, the characteristics of which are relevant for the risk assessment.  Likewise, Friedman [#9510] rightly draws a distinction between gene drives to suppress a population of mosquitoes and gene drives to suppress the disease-causing parasite (“replacement drive”)
There have been a number of submissions listing potential adverse effects, see for example Helmut Gaugitsch [#9540], and Margret Engelhard [#9577]. Depending on the case, one or more of those potential adverse effects may need to be considered in the risk assessment, looking at likelihood of occurrence, the consequence of it occurs and whether any identified risks are acceptable or manageable. As regards the ‘acceptable’ it is very important that we keep in mind that risk assessment is comparative, i.e. that we compare any identified risks with appropriate comparators.
Yet, we should remain aware that we are still talking about projections. As Boet Glandorf [#9500] put it very clearly: at this moment there is no existing information on impacts on the conservation and sustainable use of biological diversity from organisms containing engineered gene drives
Further, as Emmanuel González-Ortega, [#9569], María Andrea Orjuela Restrepo [#9551], Louisa Matthew [#9529] and others have rightly observed, in the case of gene drives the risk assessment can draw on the significant knowledge that we have gained about invasive species, non-LMO biological agents, exotic species, ecosystem resilience, et cetera.
In this respect an observation in relation to the often quoted ‘off target effects’. I fully support the observation by Camilla Beech [#9539] and others that an off-target change in the genome is not necessarily a negative impact in itself. I also agree with Kirsi Törmäkangas [#9538] while off-target issues and unintentional effects are certainly crucial in e.g. gene therapy and animal breeding, they may be less relevant in plant breeding, where subsequent selection and crossing is anyway practiced to remove unwanted effects from the cultivars.

Likewise, I fully support the notion put forward by several colleagues that in many cases field research is the only way to get reliable data for risk assessment.

Looking forward to the next exchanges and wishing everyone a good remainder of the weekend!

Piet

Dear All,
having followed the various contributions from a governance perspective I’d like to submit the following observations:
There is a difference between self-regulation by researchers and developers  and state-based regulatory oversight. The former can and should be open and flexible, the latter must be precise with predictable outcome. Researchers and developers when suggesting elements of regulatory oversight tend to underestimate the internal logic of the law such as doctrinal consistency, guidance by fundamental rights and principles (eg precaution, proportionality), distribution of burdens of proof, respect for levels of regulatory competences within states and regions, procedural safeguards, access to court review, etc.
Regulatory oversight of genetic engineering is very different in different states. There is only limited space for developing common global standards other than very general procedural and material principles. Any harmonization effort should allow for a plurality of approaches.
The following questions on regulatory oversight for synthetic biology may be considered:
1. Should the scope of oversight include products from cisgenesis? Should it include certain non-living bioparts, protocells etc ?
2. If the scope of oversight is broadly defined what processes or products should be exempted or subjected to a facilitated regime (such as notification rather than prior authorization)?
3. Should gene drive systems aimed at being released into the environment be kept in containment until appropriate regulatory tools have been established. Must the usual risk classes and requirements for containment be adjusted to the specific risks of gene drives?
4. Considering that the often made reference to case by case risk assessment cannot dispense from regulatory guidance: How should the current risk assessment methodology be revised in view of new risks from SynBio techniques and products?
5. Considering that some regulatory concepts (such as the European) only look at health and environmental risks while others (such as the US) provide for a risk-benefit weighing: what are the pros and cons of the two systems?
6. If an assessment of benefits is introduced: Should it allow for any benefit, including economic profit, or should only justifiable use-values be considered?
7. What information must be submitted to allow for a benefit assessment, and what assessment methodology would be appropriate?
8. What kinds of direct and indirect benefits for biodiversity protection and enhancement should be accepted? How should they be assessed? Should there be proof of effectiveness, and through what evidence? How can the affected (often indigenous) communities be involved? 
9. If benefits and risks shall be weighed up: What is the common denominator? Should benefits be able to outweigh any adverse effects on the environment, or only residual or negligible risks?
10. If benefits and risks shall be weighed up: Should alternatives be tested that allow for reaching benefits at lower risks?
11. Should not only health and environmental but also socio-economic side- effects of SynBio products be considered as a regulatory requirement? This would be new in many regulatory systems (including the EU) because they consider this to be a matter of the market. If so how could the negatively affected persons be involved in the procedures?
12. Is it appropriate to delink risk regulation from the regulation of access to genetic resources and benefit sharing (“ABS”)?
13. Is it correct to say that risk regulation is tied to genetic resources as material (because only material can cause damage), while ABS regulation must relate to both genetic resources as material and as information?
14. Is information on genetic resources a kind of intellectual property of the country of origin of the material if the same country determines this by way of its access legislation and agreements?
15. Is it nevertheless illusionary to establish a system of tracing products back to countries of origin considering the multiple flows of genetic information (“DSI”) through data bases?
16. Considering this, should a multilateral system be established that would allow for free use of any genetic information but require the payment of a charge for marketed products and patented information, the payments being collected into a fund?
17. For what pruposes should the fund be allocated (preservation of biodiversity, organic agriculture, indigenous communities, etc)?
Best regards
Gerd

Synthehtic Biology could have positive effects on conservation of biological diversity, especially on bioremediation or biodegradation issues (  http://www.oecd.org/sti/emerging-tech/45144066.pdf), reduce of plastic waste (https://www.researchgate.net/publication/326689242_P4SB_-_From_Plastic_waste_to_Plastic_value_using_Pseudomonas_putida_Synthetic_Biology) ,  CO2 fixation (  https://www.ncbi.nlm.nih.gov/pubmed/27787752), nitrogen symbiosis (https://www.ncbi.nlm.nih.gov/pubmed/24687978 ) and others;  however, SB should  be used in order to contribute biological diversity components conservation. We must prioritize and not interfere evolution processes, maintain socio ecological systems resilience, taking account functions and structure of ecosystems. The key rol have the risk assessments and risk management case by case in long term. The Amazonian and Andean Mountain ecosystems should have especial considerations, included protected areas.
I would like to highlighted: “According to the National Academy of Sciences, “there is insufficient evidence available at this time to support the release of gene-drive modified organisms into the environment,” and a considerable amount of research and evaluation is still necessary” Mr. Lazaro Regalado, Cuba [#9563].

Sustainable use of biological diversity components means “the use of components of biological diversity in a way and at a rate that does not lead to the long-term decline of biological diversity, thereby maintaining its potential to meet the needs and aspirations of present and future generations” (https://www.cbd.int/convention/articles/default.shtml?a=cbd-02) . In this regard, SB should not affect the long term decline of biological diversity components. It is more important and crucial to use natural live organisms or products than SB organisms. The products develop in confined field trials could have better control than open field release; hence, I think we need to discuss regarding precautionary principle United Nations the interference of SB organisms in the evolution (https://www.igi-global.com/article/sustainability-anticipatory-governance-synthetic-biology/67354).
Fair and equitable sharing of the benefits arising out of the utilization of genetic resources, is the third objective of CBD. SB technology is related with patents (https://www.sciencedirect.com/book/9780080444741/advances-in-synthetic-organic-chemistry-and-methods-reported-in-us-patents#book-description). The patents are vital incentives to develop innovations; in this context, it could be possible to share some benefits to origin countries where the genetic resources were developed to biological diversity conservation through an international fund.

Dr. Marina Rosales Benites de Franco
Universidad Nacional Federico Villarreal

Dear Colleagues
I welcome the logical breakdown of regulatory oversight factors provided by Gerd Winter [#9590].
Kind regards, Dan.

Dear all

Thanks to our moderator for ably summing up [#9584] - it is clear that there are not yet applications for release of LMOs containing engineered gene drives, but the research is currently at the laboratory stage. Nonetheless, there are numerous questions about regulatory oversight that need to be answered, and governance arrangements worked out, before we come to the point of release, as highlighted in #9590. I would add that this includes the issue of obtaining the free, prior and informed consent of indigenous peoples and local communities, in the cases where their lands and territories, or resources, may be affected, as well as that of the prior informed consent of all potentially affected states, because of the high potential for unintentional transboundary movements with those gene drives that have a high propensity for spread.

Furthermore, as research is currently at the laboratory  stage, this makes the regulation of contained use activities all the more important. There are no internationally agreed standards for contained use specific to LMOs containing engineered gene drives. This is an urgent priority that needs to be addressed. At the national level, one option for governments is to require licensure of experiments involving LMOs containing engineered gene drives. Review and approval of such contained use applications by a national body enables more thorough, consistent and unified government oversight.

Kind regards
Lim Li Ching
Third World Network

Dear colleagues,

this has been a very intense discussion, thank you, Maria, for enabling and guiding this.

Further to my input in the discussions in topic 3 – which I would like to cross-reference here rather than repeat myself – I would like to add a few more points.

With regards to gene drives, CRISPR/Cas9 is primarily known for enabling the homing drive system, i.e. where the drive element keeps copying itself across to the homolog chromosome should it not already be there.

CRISPR/Cas is though also increasingly being utilised (or envisaged) in the development of other gene drive systems, such as autosomal or Y-linked X-shredder (where CRISPR/Cas will act as a nuclease and simply cut target sites on the X-chromosome with the purpose of destroying it and thus having male offspring only), or as toxin-antidote systems to enable underdominance drives or sex-ratio distorters (see Marshall and Akbari 2018).

Given its prominence in synthetic gene drive systems, on prospect of releasing a number of gene drives into the wild is the rapidly increasing load of active CRISPR/Cas9 endonucleases in the environment. What does that mean? Will they increase the backround mutation rate in its carriers, even when the target site has evolved resistance? Will they lead to occurences of off-target effects? Valle et al. (2017) is just one of the authors asking this question, stating that research should seek to find answers to this.

Whilst countermeasures to this have been conceptualised, they have reamained entirely theoretical, lacking any proof of concept, such as the so-called daisy restauration drive (Min et al. 2017).

The issue of dual use – ie milirary use - is also of importance to stay aware of.

One final point is that of the intended use of synthetic gene drives to eliminate pests -in particular insect pests- from agricultural places. Are GDOs thus becoming the new ‘pesticides’? What about secondary pests (a common and quick evolutionary response), will that call for a new round of gene drives? What are the consequences of such an approach for agricultural ecosystems and for agriculture dependent or interacting biodiversity?

There are many questions that need raising, also regarding consequences for ecosystem resilience or nutrient cycling, in particular with self-spreading drives, but not only.

I am looking forward to further discussions on the next topics.

With best regards,

Ricarda Steinbrecher
Federation of German Scientists

Marshall, J. M., and O. S. Akbari. 2018. "Can CRISPR-Based Gene Drive Be Confined in the Wild? A Question for Molecular and Population Biology." Acs Chemical Biology no. 13 (2):424-430. doi: 10.1021/acschembio.7b00923.

Min et al. 2017. https://www.biorxiv.org/content/early/2017/03/10/115618.full.pdf

Vella MR, Gunning CE, Lloyd AL, Gould F. 2017. Evaluating strategies for reversing CRISPR-Cas9 gene drives. Sci Rep 7: 8.

Dear forum participants,

Thank you for your interventions. This topic is now closed for comments.

Secretariat

POSTED ON BEHALF OF Ms. Yolanda Teran, La Red de Mujeres Indigenas sobre Biodiversidad de America Latina y el Caribe (Note: this message arrived at the Secretariat before the closing of the discussion.)
************************************
As a community member of Kichwa Indigenous Nation from Ecuador I am aware that new techniques, developments and applications on the field of Synthetic Biology are new to us, Indigenous Peoples. We know that our ancestors used technolgy having in mind the culture, the livelihoods and development the core was happiness, security, reciprocity, good health and happiness.

Regarding Synthetic Biology there are uncertanties about the positive and negative impacts and effects of these technologies, uses and secure containers. There is a huge gap between Western scientists and Indigenous Peoples and Local Communities, in one hand there are labs, technical staff, trainned professionals, budget, commerce, profits, on the other hand there is our traditional knowledge and our advocacy (men, women, youth and elders) to defend our  life and survival and to having a  healthy environment. We do not have budget and or personnel to work in this field, however we are already aware of the soci-economic impacts of these nethe preservation and care of Mother Earth and all her ecosystems. These technologies were done following the wisdom ofthe elders, the Indigenous scientists and the solar and lunar calendar, any innovation was made for the collective well being of the humanity and the Nature. This means that in the w products known by our people as "plastic things".

In the last AHTEG meeting we put on the table and explained our views. cosmologies and epistemologies to be included in the final report. At this time I would like to reiterate that any activity to be done in our lands, territories and waters must have a study of impact (Ake:Kon Guidelines) and comply with the process of consultation, free, prior and informed consent and get clear and well defined  terms of mutual agreement (UNDRIP Art 3, 31..., CBD, Nagoya Protocol). We have the right to veto of the activity goes against our well being, Sumak Kawsay too.
We also need to be aware that the impact of Synthetic Biology will be on all worlds of the Indigenous Universe, on all sacred directions and in all inhabitants of Mother Nature.
The discussions are in English which is limiting the participation from Latin America and the Caribbean.
Yolanda