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.

In relation to the discussion on this topic, it will focus on undertaking a review of the current state of knowledge by analysing information, including but not limited to peer-reviewed published literature, on the potential positive and negative environmental impacts of current and near-future applications of synthetic biology, including those applications that involve organisms containing engineered gene drives. The discussion should also take into account human health, cultural and socio-economic impacts, especially with regard to the value of biodiversity to indigenous peoples and local communities.
Also for this topic, participants are asked to share as much information as possible, including articles, and other materials. A good review is dependent on relevant and high-quality input. Synthesis of data is an important step when reviewing the current state of knowledge. Lack of knowledge may also be a relevant factor.
Some guiding points and questions:
• How do we get the "right picture", the current state of knowledge?
• Probably, there are mixed views on what is the "right picture".
• How to obtain an influx of relevant information from a good variety of sources?

Thank you,

Casper Linnestad

Dear Caper,

thank you for this opportunity for us to discuss how we get the "right picture" .

I would like to focus my comments on IPBES  regional reports as I was involved in the assessment as CLA.

In short, there has been either absent/limited discussions on the Syn. Bio and topics (or genetic resources in generally are largely limited to assessments of the status in the reports, in my humble personal view).    Please correct me if others have different views. 
  
Documents -----------
Four regional reports were adopted in March 2018, and Their Summary for Policy Makers [SPM] is endorsed by the member states (Please note that the member states are different constituency from the Parties to the  CBD).   The main reports are also available in English now.

[Regional Assessment reports]
https://www.ipbes.net/deliverables/2b-regional-assessments

Dear Participants,

I am pleased to have another chance in contributing to the ongoing discussions on Synthetic Biology as it relates to the state of knowledge in the field.

As a regulator in the area I am guided, as do many others in the field, by the Biosafety Protocols (Cartagena Protocol on Biosafety and the Supplementary Protocol on Liability and Redress), which Nigeria signed and domesticated. These international guidelines, negotiated and articulated by scientists and legal professionals representing Parties, clearly stated that sound scientific evidence should be the basis for assessing risks associated with any LMOs.

Mr. Rodrigo in his submission (#9561) has graciously pointed out relevant sections of the Supplementary Protocol and enumerated criteria for determining positive impacts of the technology. I quite agree with him on the pertinence of using sound scientific evidence in assessing risks as it relates to Synthetic Biology and other aspects of modern biotechnology.

Thank you.
Chinyere

Dear Casper and colleagues,

Thank you for guiding us on 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 Casper Linnestad and other colleges,

Initially, thank you very much for bringing the discussion and all colleagues to share their knowledge.

In my opinion, I believe Synbio is a natural evolution of the technologies and techniques that we use to overcome challenges. The application of Synbio has numerous positive impacts in the most different fields, such as: sustainable use; conservation; human, animal and plant health; public health, food production; combating infectious diseases and pests; production of vaccines and new medicines, among others.

The possible negative impacts can be avoided by analyzing case by case and scientifically the proposed uses. Adopting prevention and management measures if something unexpected happens. That is, the same principles that we use with Modified Living Organisms (LMOs) and that we already have a lot of experience.

Some Synbio techniques can be used to change the proportion of gene distribution in future generations. And that's Gene Drive.

One of the most promising uses of gene drive technology is the possibility of controlling populations of organisms. Through this approach it is possible to: eradicate invasive species that destroy the biological diversity of a given ecosystem; conserve endangered species; support agriculture by reversing pesticide and herbicide resistance in insects and weeds; control damaging invasive species; to help combat pests that threaten food production; and to modify species that transmit important infectious diseases (notably mosquitoes that transmit malaria, dengue, and zika pathogens) to stop this action9.

Another important issue of gene drive approach is its ability to spread a characteristic of interest. In this way, it is possible to use the same gene drive technique, but with a different strategy, to modify organisms preventing them from transmitting infectious diseases, as demonstrated by the Target Malaria10, and to combat pests (herbivorous and disease-vectoring insects, pathogens and weeds) that attack agriculture11.

Faced with so many benefits of using gene drive technology, scientists and regulators have kept the necessary caution to the subject due to the possibility of off-targets and species eradication. Therefore, ways for better controlling the technique are being developed so that there is greater understanding and control (spatial and temporal) in order to limit undesired consequences13.

Another initiative to help improve the understanding of the gene drives approach is the CBD's proposal to discuss the topic and check the possibility of developing a guideline to gene drive.

References:
9 - Gene drives in our future: challenges of and opportunities for using a selfsustaining technology in pest and vector management. James P. Collins. BMC Proceedings 2018. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069294/)
10 - Target malária. Malaria: a Deadly Disease. https://targetmalaria.org/.  accessed February 14, 2019.
11 - Gene drive systems: do they have a place in agricultural weed management? Paul Neve. Pest Manag Sci 74. 2018. (https://onlinelibrary.wiley.com/doi/epdf/10.1002/ps.5137)
12 - “Elimination of HIV-1 Genomes From Human T-Lymphoid Cells by CRISPR/Cas9 Gene Editing” Kaminski, R., Y. L. Chen, T. Fischer, E. Tedaldi, A. Napoli, Y. G. Zhang, J. Karn, W. H. Hu, and K. Khalili. 2016. (https://www.nature.com/articles/srep22555.pdf)
13 - Engineered reciprocal chromosome translocations drive high threshold, reversible population replacement in drosophila. Buchman AB, Ivy T, Marshall JM, Akbari O, Hay BA. BioRχiv 2016. (https://pubs.acs.org/doi/pdf/10.1021/acssynbio.7b00451)

Dear Casper Linnestad and other colleges,

I do paraphrase the text of Marcelo Henrique Aguiar de Freitas

Kind regards,

Elibio Rech

Topic 3:  review of the current state of knowledge...

Thank you Casper for your guidance in approaching this question with its many additions (to the short title above) and with respect to getting the ‘right picture’ of the current state of knowledge.  By that expression, I am thinking you mean the importance of getting the right balance and context or as you put it in bullet three,  “to obtain an influx of relevant information from a good variety of sources”.  I agree with you.  The other point to make, similar to the one we discussed in topic 2 regarding options for carrying out regular horizon scanning, is that the ‘review of the current state of knowledge’ is essentially the starting point for the horizon scanning.  This can largely be automated with a simple search algorithm to scan the published literature for certain key words (or, as we used to do in my graduate students days, get the most recent version of ‘Current Contents’ and search for any relevant key words).

The other part of the question for this topic deals with “…potential positive and negative environmental impacts of current and near-future applications of synthetic biology…” and in this context I think it important to build on our 2015 AHTEG report that addressed potential positive and negative environmental impacts on several pages (UNEP/CBD/SYNBIO/AHTEG/2015/1/3 pages 6-10) and for this topic we should focus on any new issues that have arisen since 2015.  Others more knowledgeable than I have already cited recent papers in this and the other on-line discussion topics and I have nothing new to add to these lists.

Thank you,
Jim Louter, Environment and Climate Change Canada

Dear participants. Thank you for submitting information and views also on topic 3. Here, in fact, we are direclty addressing paragraph c) in the terms of reference of the Ad hoc Technical Expert group of Synthetic biology (Decision 14/19), i.e. the

"…current state of knowledge by analysing information, including but not limited to peer-reviewed published literature, on the potential positive and negative environmental impacts, taking into account human health, cultural and socioeconomic impacts, especially with regard to the value of biodiversity to indigenous peoples and local communities, of current and near-future applications of synthetic biology, including those applications that involve organisms containing engineered gene drives."

Hence, in principle, the effect spectrum to be taken into account is very broad!

I agree with Xu (#9493) that many of the ongoing applications of synthetic biology are within industrially contained facilities, without any direct environmental effects. However, please keep in mind that the scope of the CBD is broader (organisms, components and products) than that of the Cartagena Protocol (living modified organisms), and also, that some synbio applications may have cultural and socio-economic impacts and effect indiginous peoples and local communities.

For inspiration, Jim (#9508) wisely suggested that we could build on the AHTEG report from 2015, and in particular, add examples to the list presented in the report on pages 6-10: https://www.cbd.int/doc/meetings/synbio/synbioahteg-2015-01/official/synbioahteg-2015-01-03-en.pdf

Please also check the latter 2017 AHTEG report, particularly pages 5-6:
https://www.cbd.int/doc/c/aa10/9160/6c3fcedf265dbee686715016/synbio-ahteg-2017-01-03-en.pdf

Some of you may feel that several of the topics 1 through 7 are tightly interwoven, and you may find it difficult or unatural to separate the discussions. In that case, please note that, for instance, whereas topic 1 was meant to capture information on new synbio technological developments, this week, under topic 3, we are focusing on the effects resulting from the applications of synthetic biology.

Thank you again for taking an interest in this online forum and being active. I very much welcome further views and value additional information!

Cheers,
Casper.

Dear Casper, thank you very much for guiding us in this discussion.
I totally agree with Jim (#9508) and support that we could build on the AHTEG 2015 report (and later 2017). But before reviewing them I would like to share with you link to the Journal of Resposible Innovation, Special Issue: Roadmap to Gene Drives: Research and Governance Needs in Social, Political, and Ecological Context https://www.tandfonline.com/toc/tjri20/5/sup1
I think articles of this Issue are very relevant to this discussion.
As for gene drivers paper "Identifying and detecting potentially adverse
ecological outcomes associated with the release of gene-drive modified organisms" https://www.tandfonline.com/doi/pdf/10.1080/23299460.2017.1415585?needAccess=true
from my point of view is interesting analytical review well structured  and can be used for discussions on risk assessment.
Best regards, Galina

Dear all,
I would like to intervene in answering the questions about the "right picture".
Information on positive impacts is more numerous and more popular because it serves the interests of multinationals and promoters of Synthetic Biology. On the other hand, we regret the lack of analysis of potential negative risks, both environmental and socio-economic. Thus, in the name of the precautionary approach, we urge the realization and dissemination of comparable studies on the risks related to synthetic biology including socio-economic analyzes. In view of sustainable development, decision-makers must decide on the basis of comprehensive knowledge

Dear moderator Casper and Colleagues,

Thanks for your guidance and also thanks Ryo Kohsaka [#9486] for his suggestion on IPBES regional reports, I agree it’s a good source of relevant information to get a "right picture"
In addition, regarding the same issue, I would like to draw the attention on a presentation about Synthetic Biology: Safety, Security, and Promise (See Attached) and mainly in the Areas for Governance pointed out in this context, it was in 2016 and in this connection a comment of today in Nature, where specialists from seven countries call for an international governance framework:
Adopt a moratorium on heritable genome editing.
14 M A R C H 2 0 1 9 | VO L 5 6 7 | N AT U R E | 1 6 5      d41586-019-00726-5.pdf

Kind regards,
Dr Lazaro Regalado

Dear Moderators and Participants,

My name is Ntakadzeni Tshidada, Department of Environmental Affairs,  South Africa.

This topic is not different from what was discussed in Topic 2.

The horizon scanning will provide us the current state of knowledge. In addition, there are number of platforms and conferences in which synthetic biology is being discussed and following up on those can provide us with o what can be a possible picture and also not limiting us to what has already being done by the 2015 AHTEG and IPBES report.

Thabk You
Ntakadzeni

Dear Casper thank you for guiding and moderating

I think synbio products shall be considered as living modified organisms and/or genetically modified organisms. If the designed synbio organisms, components and products are from known amino acid sequence and/or RNA and cells, the synbio organisms, components and products will ultimately have had so similar that the structure, function, genome, proteome, metabolome and phenome of an existing product in nature with increased efficiency, this shall require as same concern as genetically modified organisms which its regulatory mechanisms has been being developed since its story. Whereas, if the designed synbio organisms, components and products, however, were from non-existing amino acids, RNA and cells, the new synbio organism will ultimately have had new characteristics for new genome, proteome, metabolome and phenome, it would require a separate biosafety protocol.

Dear all,

I just posted the followoing message under topic 4, which was meant for topic 3. Sorry for that.
To be sure you see it, I post it once more, now really under topic 3:.

Original message:

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

POSTED ON BEHALF OF Ms. Ruth Spencer, Antigua and Barbuda:
*********
Greetings Dear Colleagues, I am Ruth Spencer, GEF/Small Grants Coordinator  from  Antigua and Barbuda. With my local community groups   organized and brought together on Feb 20th, 2019  our local beekeepers from the Beekeeping Cooperative and other local community persons with the government technicians and key stakeholders  to  learn , share and find solutions to  impacts on our pollinators form toxic chemicals being used for fogging for mosquitoes. They  are killing the bees and other insects pollinators. We have good buy in from the various government departments and alternatives are being looked at, in addition to a  stock taking of what chemicals are currently in stock with  more attentions to what is ordered by the government and  coming into the country. In addition the Pesticides and Chemical Board will be increasing vigilance at our ports with customs officials to  imports of  what chemicals and pesticides are coming into the country. This is a start and as we grow and develop our capabilities, we commit to do more.

Dear Colleagues,

Regarding the current state of knowledge about the different positive and negative effects of Synthetic biology I think that the a large extend we are at the same situation as in 2017 when very few if any synthetic biology organisms have been released into the environment. At the same time we have some new information which can be instructive. Kyrou et al. (A CRISPR-Ca9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes, Kyrou et al., Nature Biotechnology 36, 1062-1066) showed that a well-designed gene drive can be very effective in a laboratory population and can lead to its collapse before any resistance is developed. Although the set-up of the experiments was highly artificial (spatially homogenous population of single species, very high initial frequency of the gene drive allele, etc.), it’s a very nice example of the step by step approach which should be taken when considering release of gene drives containing organism. Potential positive effects are very significant if such collapse of the wild populations of important pathogens as Plasmodium translates into reduced morbidity (the population size of the vector is just one of the factors that determine the malaria prevalence).
The negative effects are hard to predict given the lack of sufficient information and the complex interactions in the ecosystems.

Best Regards,
Nikolay

Dear All,
I am a scientist, working in the Institute of Virology, Biomedical Research Center of the Slovak Academy of Sciences, institution devoted to basic and applied research in biomedical sciences. The principal mission of this research center is to foster research excellence, develop interdisciplinary approaches, and stimulate innovative potential for the improvement of our knowledge on human diseases, its better translation to clinic and more effective practical use for benefit of patients and the entire society.  
I was fortunate to have had the opportunity to participate in both the 2015 and 2017 Synthetic Biology AHTEGs.
I am also 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. Dear Casper thank you for guiding and moderating,
Regarding the current state of knowledge about the different positive and negative effects of Synthetic biology I think that we are only to some extend at the same situation as we were in 2017. A very few if any synthetic biology organisms have been released into the environment. May be but, there are certain „spot light“ attempts, that were recently (2018-2019) published, causing questions, wrinkles, cheers - all depending to whom you speak about (administrators, green peace members, scientists) e.g.:
https://www.nature.com/articles/d41586-018-07545-0
https://www.nature.com/articles/d41586-019-00726-5
http://science.sciencemag.org/content/sci/363/6429/884.full.pdf

Others more knowledgeable than I have already cited further recent papers in this and the other on-line discussion topics and I have nothing new to add to these lists.

As Nicolay wrote [#9534], and I agree with him: “The negative effects are hard to predict given the lack of sufficient information and the complex interactions“ (by taking into account human health) „in the ecosystems“.


Best regards,
Zuzana Sekeyova

Dear colleagues,

thank you Casper for guiding us through this important discussion.

My contribution may also be partly relevant for the parallel discussion under topic 4.

First of all I would like to support those who have suggested that we build on the compilation on this subject undertaken and put together by the AHTEG at its Meeting in 2015, but also in 2017.

In addition I would like to share the following observations, focusing on gene drive:

Environmental impacts, including those on biodiversity, of organisms containing engineered gene drives (gene drive organisms; GDOs) are likely to occur if GDOs are developed that intentionally alter wild populations and are able to spread in an unlimited manner. The intended genomic changes have the potential to alter not only target populations and species but also non-target species, in case cross-breeding or hybridisation occurs between species. Gene flow between individuals and transfer of the gene drive mechanism together with cargo genes within a target population is the inherent and intended characteristic of all gene drive applications. Gene drive applications which aim at suppressing target populations of vector-transmitting mosquitoes may also affect related species, as hybridization and interspecific gene flow between different mosquito species have been documented. Also intraspecific hybridization within mosquito species is likely to be of relevance.
Due to the self-sustaining character of the edited genome in GDOs, evolutionary responses of organisms to the gene drive mechanism have been considered. The occurrence of resistance to gene drive applications is one of the most frequently discussed risks of this technology. Resistance can compromise the functionality and effectiveness of the GDO and of the potential disease control strategy, in case human pathogen vectors are targeted. This may have profound implications for human health. Also long-term epidemiological consequences, e.g. due to altered virulence or transmission of pathogens to mosquitoes and humans have been predicted, as well as changes in the biology of the vector (e.g. host range, “vector-switching”). In addition, impacts on existing control strategies of pests or disease-carrying vector species may be relevant, such as a reduction of the conventional management efficacy. Biosafety risks of GDOs may be similar to those of other LMOs, however raising additional concerns due to their potentially unlimited spread through wild populations and ecosystems. Such risks refer to the complete eradication of species, negative impacts on non-target populations, other organisms and biodiversity. For example, food chain effects such as the loss of prey and important food sources for higher trophic levels may be relevant when applying suppression drives. Depending on the specific application, effects on predators, prey species, competitors or complex ecological functions may occur. The depletion of local or global populations of native and wild species communities, genetic diversity and changes in ecological interactions have been mentioned. Evolutionary responses may also refer to changes in mating systems of target plant populations as response to suppression drives. In particular, major ecological threats due to the unanticipated behaviour and uncertain effects of GDOs cannot be excluded if GDOs become invasive in wild populations.

Cultural and socioeconomic impacts:

For releases of GDOs also other than environmental and human health implications have been discussed. The fact that GDOs can spread at long distances and across geographic regions implies that GDOs can potentially affect communities beyond the targeted release area. This triggered concerns regarding the regulation, governance, and control of GDO releases.  Scientists therefore call for an early and extensive involvement of stakeholders and local communities when releases are planned. Socio-cultural concerns and economic issues such as benefits and welfare impacts for GDOs have also been addressed, as well as implications for other types of agriculture, such as organic farming. 

Literature

Baltzegar J., Barnes J. C., Elsensohn J. E., Gutzmann N., Jones M. S., King S., Sudweeks J. (2018). Anticipating complexity in the deployment of gene drive insects in agriculture. J. Responsible Innovation 5 (S1): 81-97
Besansky, N. J., Lehmann, T., Fahey, G. T., Fontenille, D., Braack, L. E. O., Hawley, W. A., Collins, F. H. (1997): Patterns of mitochondrial variation within and between African Malaria vectors, Anopheles gambiae and A. ambiensis, suggest extensive gene flow. Genetics 147 (1817): 1817-1828.
Bull, J. J. (2015): Evolutionary decay and the prospects for long-term disease intervention using engineered insect vectors. Evolution, Medicine, and Public Health. Doi: 10.1093/emph/eov013
Bull, J. J. (2016): Lethal gene drive selects inbreeding. bioRxiv. Doi: 10.1101/046847
Callaway, E. (2017): Gene drives meet the resistance. Nature 542:15.
Courtier-Orgogozo V , Morizot B, Boëte Ch (2017). Agricultural pest control with CRISPRbased gene drive: time for public debate. Should we use gene drive for pest control? EMBO Reports, May 16, 2017
David, A. S., Kaser, J. M., Morey, A.C., Roth, A. M., Andow, D. A. (2013): Re-lease of genetically engineered insects: a framework to identify potential ecological effects. Ecology and Evolution 3 (11): 4000-4015.
ETC Group (2018). Forcing the Farm. How Gene Drive Organisms could entrench industrial agriculture and threaten food sovereignty. ETC Group and Heinrich Böll Foundation, October 2018. http://www.etcgroup.org
Kofler N., Collins J. P., Kuzma J., Marris E., Esvelt K. et al. (2018). Editing nature: local roots of global governance. Science 362 (6414): 527-529.
Lehmann T. et al. Wind-borne migration of mosquitoes and pathogens: Potential for bio-surveillance.  2018 ESA, ESC and ESBC joint annual meeting, Vancouver, November 14, 2018.
Mitchell P. D., Brown Z., McRoberts N. (2018). Economic issues to consider for gene drives. J. Responsible Innovation 5 (S1) 180-202
Miles, A., Lawniczak, M. K. N., Donnelly, M., Kwiatkowski D. (2016): Natural diversity of the malaria vector Anopheles gambiae. bioRxiv. Doi: 10.1101/096289.
Murphy, B., Jansen, C., Murray, J., De Barro, P. (2010): Risk analysis on the Australian release of Aedes aegypti (L.) (Diptera: Culicidae) containing Wolbachia. http://www.cisro.au

NAS (2016): Gene Drives on the Horizon: Advancing Science, Navigating Un-certainty, and Aligning Research with Public Values. Washington DC. Doi: 10.17226/23405
Najjar D., Normandin A. M., Strait E. A., Esvelt K. M. (2017). Driving towards ecotechnologies. Pathogens and Global Health 111 (8): 448-458
Noble, Ch., Olejarz, J., Esvelt, K. M., Church, G. M., Nowak, M. A. (2017): Evolutionary dynamics of CRISPR gene drives. Science Advances 3: e1601964.
Oliveira, E., Salgueiro, P., Palsson, K., Vicente, J. L., Arez, A. P., Jaenson, T. G., Caccone, A., Pinto, J. (2008): High levels of hybridization between molecular forms of Anopheles gambiae from Guinea Bissau. Journal of Medical Entomology 45 (6): 1057-1063.
Oye, K. A., Esvelt, K., Appleton, E., Catteruccia, F., Church, G. M., Kuiken, T., Lightfoot, S. B. Y., McNamara, J., Smidler, A. L., Collins, J. P. (2014): Regulating gene drives. Sciencexpress. Doi: 10.1126/science.1254287
Simon S., Otto M., Engelhard M. (2018). Synthetic gene drive: between continuity and novelty. EMBO reports 19:e45760, p 4

I am looking forward to our further discussions during this week and the two weeks to follow.

Best regards to all

Helmut Gaugitsch
Environment Agency Austria

Dear all,
In response to Helmut Gaugitsch's post #9540, which is specifically looking at the potential negative impacts on mosquitoes containing a gene drive mechanism, I would like to share some literature on the topic of mosquito ecology and biology.
The question of hybridisation of Anopheles gambiae s.s. with other mosquitoes has been raised before and would certainly be part of a risk assessment prior to any application for the field evaluation of gene drive mosquitoes. The gene flow between Anopheles gambiae and other mosquito species has been studied and has led to a number of publications. Anopheles gambiae is known to have limited hybridisation in the wild, due to pre-mating barriers (such as single-species swarms and different habitat preferences). It is known to hybridise in the wild with Anopheles coluzzi which is also a targeted vector for malaria control. Outside the Anopheles gambiae complex, other mosquitoes are too distantly related to mate with species within the complex and transfer genes. The factsheet attached here presents those existing data and provides a number of useful references on the existing entomological knowledge.
In relation to the question raised about the food chain, a recent publication (Collins et al. 2018) made a literature review of the knowledge about the ecology of the Anopheles gambiae complex (the targeted species for malaria control in Africa) and the potential impact of its local removal from a population. It concludes that there is no evidence that removal of the species could have an impact on the food chain, and highlighted the comparison with the impact of existing vector control methods.
Warm regards
Delphine

My name is Dr Tom Wakeford from the ETC Group. During fieldwork over the last twenty-eight years I have developed expertise is in ecology, biodiversity conservation, genetics and transdisciplinary approaches to research.

Thanks to everyone for their contributions and thank you, Casper, for your guidance.

I write with reference the article cited in Ms Delphine Thizy’s comment [#9580] with reference to the impact of one example of synthetic biology. Collins et al.  do not refer to gene drive organisms themselves, but more vaguely to “new genetic control methods”.  Furthermore, the article is from a journal that describes its focus as being on “the biology and control of insects, ticks, mites and other arthropods of medical and veterinary importance”. Research on the conservation of biodiversity does not appear to be the journal’s primary purpose.

In my judgement, Ms Thizy’s contribution risks confusing two kinds of food chain: i) the concern that both the CBD and this forum have about the potential threat of synthetic biology to biodiversity as it relates to agricultural systems (the human ‘food chain’) and ii) the localised effects of removing a disease vector, given that it is part of the ‘food chain’ for other organisms. 

The effects on biodiversity conservation and sustainability would appear much more far-reaching for the first meaning of ‘food chain’ than for the second.

The decline of biodiversity associated with monocultures, industrial chemicals and made worse by the use of genetic modification, has been well documented by some of the world’s most respected conservationists over several decades (Moore 1987, Janzen and Winnie 2019).

Many studies, such as those recently reviewed by Lundgren and Fausti (2015), suggest that a high level of biodiversity is important for the control of pests in agriculture. Agroecological approaches to food production enhance biodiversity and hence remove the need for application of chemical pesticides or synthetic biology, such as gene drive organisms.

Researchers at ETC Group and many others have gathered evidence about the likely effects of the deployment of synthetic biology on the biodiversity of agricultural systems (ETC 2018, Mooney 2018). We conclude that synthetic biology in general, and gene drive organisms in particular, would be likely to lead to the further intensification in the use of monocultures and industrial chemicals. This would in turn cause a further and potentially even more dramatic reduction in biodiversity than we have seen in recent years.

We would respectfully suggest that that one review article, which suggests a lack of evidence for the local effects of eradicating one species of mosquito species, is somewhat missing the point, given the systemic threat synthetic biology appears to pose to biodiversity conservation in both agricultural and non-agricultural ecosystems.

Drawing on their total of one hundred years of intense study of insect biodiversity, Janzen and Winnie conclude their article in the journal Biological Conservation with these words:

"If our terrestrial world remains one that is constructed through constant war with the arthropod world, along with the plants, fungi and nematodes, together being 95%+ of the species of Eukaryota, human society will lose very big time" (p.107).


With best wishes,


Tom

Dr Tom Wakeford
ETC Group and University of Exeter, UK.



References:

ETC Group (2018) Forcing the Farm: How Gene Drive Organisms Could Entrench Industrial Agriculture and Threaten Food Sovereignty. ETC Group.  http://www.etcgroup.org/content/forcing-farm

Janzen, D, & Winnie, H. (2019) Perspective: Where Might Be Many Tropical Insects? Biological Conservation 233: 102–8.

Lundgren, J., & Fausti, S. (2015). As biodiversity declines on corn farms, pest problems grow. The Conversation. http://theconversation.com/as-biodiversity-declines-on-corn-farms-pest-problems-grow-45477

Mooney, P (2018). Blocking the Chain: Industrial food chain concentration, big data platforms and food sovereignty solutions. Rosa Luxemburg Foundation, INKOTA, ETC Group.
https://www.rosalux.de/en/publication/id/39385/blocking-the-chain-agriculture-40-1/

Moore, N. W. (1987). The Bird of Time: The Science and Politics of Nature Conservation - A Personal Account. CUP.

Dear moderator Casper and other colleagues,

Regarding the current state of knowledge and the "right picture" is important, in my humble view, to start with the conception of near, medium and long term application of Symbio, to look only at the current state is a limitation that could be costly for biodiversity and the human health, that’s why we are also working in the horizon scanning. An interesting approach in this regard can be found in Preparing for Future Products of Biotechnology http://www.nap.edu/24605 “The task of this committee was to look into the future and describe the possible products of biotechnology that will arise over the next 5–10 years” ….“Given the rapid (and often unforeseen) advances of the past 5–10 years, it is clear that making accurate predictions of what will be possible is a difficult task, but some trends are clear: there will be a profusion of new products that will in many cases be very different in terms of their type, scope, and complexity, and the number of actors who will be able to contribute to biotechnology will be even more diverse as engineering biology becomes more accessible. At the same time, there is increased public awareness (and in some cases controversy), and the regulatory agencies are faced with the challenge of balancing the many competing interests from industry, society, government, and academia.”

A presentation of Prof Paul Thomas Director, SA Genome Editing University of Adelaide, Australia about CRISPR/CAS9 genome editing could contribute to this issue.
(See attached)

Warm regards,

L. Regalado

This message has been posted on behalf of: Mr. Lazaro Regalado, Cuba

Please find a single document attached for the purposes of sharing.

Dear Casper and colleagues,

In my opinion Synthetic biology, brings with it a series of challenges, opportunities and concerns that can be managed correctly to the extent that we have a greater knowledge and understanding of its scope, then I expose some positive or negative impacts that can be derived from Synthetic biology:

• Regarding the impacts derived from Synthetic Biology on the environment, the recreation or design of pathogenic microorganisms such as bacteria or viruses can be given, to be used as biological weapons, to which they can confer unique characteristics such as resistance, the capacity of transmissibility, toxicity and evasion to the immune response or the degree of virulence. (NASEM, 2018).

• The development of microorganisms designed for bioremediation, production of hydrocarbons or biosensors capable of contributing to the control of pollution (Schmidt, 2010).

• Many biochemical compounds can be designed either from the recreation of known metabolic pathways, recreating new metabolic pathways or through in situ synthesis of the compound. Within this type of chemical compounds are for example toxins, anti-metabolites or controlled chemicals. In the case of toxins in general, its potential is considered dangerous, while in the case of anti-metabolites and controlled chemicals, it may have medicinal or therapeutic uses, however, depending on the use that is desired or the objectives of research, the production of this type of chemical substances can have beneficial implications as worrisome (NASEM, 2018).

• Through the use of technologies based on Synthetic Biology, it is possible to synthesize ingredients that were previously obtained from natural resources, in order to reproduce flavors, fragrances, oils or sweeteners of high commercial value through the genetic alteration of microorganisms ( seaweed or yeast), which have a genetic system with alternative metabolic routes designed in silico so that the products of interest are produced, which reduces the need to resort to the flora or natural substance, thus producing a direct impact on Biodiversity (BICSBAG, 2018).

Bibliography.

National Academies of Sciences, Engineering, and Medicine (NASEM); 2018; Biodefense in the Age of Synthetic Biology. Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/24890.

Building International Capacity on Synthetic Biology Assessment and Governance (BICSBAG) Project; 2018; ¿Qué significa la biología sintética para América Latina y el Caribe?;  Documento en línea: http://www.synbiogovernance.org/wp-content/uploads/2018/06/ETC_SyntheticBiologyLatinAmericaSpanish_4F-Reducido.pdf

Building International Capacity on Synthetic Biology Assessment and Governance (BICSBAG) Project; 2018; Impulsores genéticos sintéticos: la ingeniería genética enloqueció Informe para los delegados del CDB; Documento en línea: http://www.synbiogovernance.org/wp-content/uploads/2018/06/ETC_GeneDrivesSpanish_2F-reduced.pdf

Schmidt, C.; 2010; La biología sintética. Las implicaciones de un nuevo campo para la salud ambiental; Salud Publica de México; 52(3).

Dear all,

Insofar as questions pertinent to Topic 3, including that posed by the moderator regarding how to obtain an influx of relevant information from a good variety of sources, I echo the opinions of those who [#9389, #9400, others] have previously expressed under Topic 2 that multiple methods should be employed; this Forum is one example and reports from relevant symposiums and workshops as suggested by [#9391] furnish additional options.

Regards,

Valeri Vasquez

Dear Casper
With regards to the question on how to get the right picture I already covered this in my previous post under the topic on Recommend options for carrying out the regular horizon scanning, monitoring and assessing of developments.

As for the current state of knowledge regarding environmental impacts of current and near-future applications of synthetic biology, I believe this need to be conducted on a case by case basis. Yet in the upcoming few lines I will try highlight some of the issues raised concerning gene drives and interference RNA technologies

Gene drives:
- Spread: A gene drive intended to affect only a local population might spread across an entire species. Many non-native species have a high likelihood of returning to their original habitats, through natural migration, environmental disruption (storms, floods, etc.), accidental human transportation, or purposeful relocation. Specimens whose reproduction/survival is compromised that somehow return to their native habitat, could unintentionally drive their species to extinction.
- Mutations: A mutation could happen mid-drive, which has the potential to allow unwanted traits to "ride along".
- Escape: Cross-breeding or gene flow potentially allow a drive to move beyond its target population.
- Ecological impacts: Even when new traits' direct impact on a target is understood, the drive may have side effects on the surroundings.

Interference RNA:
- Immugenicity: dsRNA identified as foreign nucleic acid, triggering an immune response
- Disruption of endogenous microRNA pathway: Exogenous RNAi molecules saturate a cell's RNAi machinery, disrupting synthesis or action of endogenous microRNAs
- Sequence specific off target effects: Similar sequences in transcriptome recognized and silenced by dsRNA

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.

On the Topic 3 on “Review of the current state of knowledge”, my personal view is that we do not seems to have sufficient scientific data on both the benefit and detrimental reports on the use of Synthetic Biology (SynBio) from the SynBio GMO biosafety perspectives especially on long term basis. This may due to SynBio GMO is rather new topic in GMO.

Hence, I am not entirely sure if we can have a “right picture” at this stage. I am keen to read more comments on this. I appreciate those who have posted references for further reading (Helmut [#9540], Zuzana [#9537], Carios [#9548]).

On the third issue raised by Casper [#9482], as the previous AHTEG member on Risk Assessment, I still think that the opinion from the that AHTEG is still valid, viz. peer-reviewed scientific articles, inter alia, are always a good source of information.

Thank you and bon weekend to all.

Regards,
Kok Gan Chan

Dear Casper and other colleagues,
I am Nina Voronova, PI at Zoology Department of Belarusian State University (Belarus) and I am happy to join the discussion. Thank you for the opportunity.

My opinion about getting the "right picture" is not really optimistic sadly. I am not sure we have or can get enough data for that. To be specific, I work in the field of pest management. We know lots of examples of extremely negative impact of the introduction of predators to new territories, for example, (one example in the added files), which was supposed to be good for the pest management but turned out as a sort of disaster for the local biodiversity. Antibiotic resistance in pathogenic bacteria and insecticide resistance in pests are another examples of getting unexpected problems from the excellent breakthrough. Now, when pesticide usage for pest management is restricted in many European countries, we come back to the idea of 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.  
Please, correct me if I am wrong, but I think we are still in the beginning of the understanding, predicting and controlling such a complex phenomena as the biodiversity dynamics. I am sure we need to put into practice long-therm research in order to develop and start to implement the multiparametric computer modelling tools for the biodiversity dynamics prediction, which are still absent.

To read: https://www.nature.com/articles/sdata2018239
https://link.springer.com/article/10.1007/s10526-018-9891-7
https://onlinelibrary.wiley.com/doi/abs/10.1111/jen.12498
Sincerely,
Nina Voronova

It is a pleasure to join the Synthetic Biology online forum and share my experience related to the proposed topics. My name is Rodrigo Carvalho de Abreu Lima, a Brazilian lawyer with 14 years of experience at the CBD negotiations and agendas.

Topic 3 relates to the state of knowledge regarding synthetic biology, its techniques, applications and products. The underlying question to be answered when searching for information related to synthetic biology at the CBD is at what extent the technologies developed through synthetic biology can pose impacts and damages to the sustainable use of biodiversity and can relate to any of the Convention objectives.

For this purpose, it is critical to access and analyze credible and science based evidences that could effectively present negative impacts, as well as positive impacts. Despite Parties already engaged in this debate over the past years, it was not possible, up to today, to build a comprehensive piece of work when it comes to damages to biodiversity that could be scientifically measured and qualified based on sound criteria.

Science is the basis of synthetic biology and, therefore, must drive it´s assessment including possible damages. Theoretical arguments with no concrete and substantiated evidences regarding effective examples of damage, measured by indicators, does not allow a proper debate around damages posed by synthetic biology.

Considering that synthetic biology is an issue being discussed at the CBD, regardless the NEI criteria had been assessed, it is quite relevant to remember the concept of damage agreed by the Cartagena Parties, within the negotiation of the Nagoya-Kuala Lumpur Supplementary Protocol on Liability and Redress.

It seems constructive to recall the history of the negotiations to inform the debates around possible damages causes by synthetic biology technologies and products. The main reason for that relies on the fact that damage must be measurable based on scientifically grounds. It is worth quoting the concepts agreed that are at the core of the Supplementary Protocol: 

Article 2.2 (b): “Damage” means an adverse effect on the conservation and sustainable use of biological diversity, taking also into account risks to human health, that:
i. Is measurable or otherwise observable taking into account, wherever available, scientifically-established baselines recognized by a competent authority that takes into account any other human induced variation and natural variation; and
ii. Is significant as set out in paragraph 3 below.

Article 2.3: A “significant” adverse effect is to be determined on the basis of factors, such as:
a. The long-term or permanent change, to be understood as change that will not be redressed through natural recovery within a reasonable period of time;
b. The extent of the qualitative or quantitative changes that adversely affect the components of biological diversity;
c. The reduction of the ability of components of biological diversity to provide goods and services;
d. The extent of any adverse effects on human health in the context of the Protocol.

The online forum and the ATHEG should use this concept as a basis when dealing with the state of knowledge and positive and negative impacts. Otherwise, the negotiations will continuously be driven by vague and intangible evidences.

When it comes to positive impacts from synthetic biology applications in crops, it is possible to quote:

• Improved soil fertility;
• Reduced chemical inputs;
• Reduced fossil fuel use;
• Reduced impacts on non-target organisms;
• Reduce and capture GHG;
• Increased efficiency of water use;
• Higher yields;
• Improve climate smart agriculture.

It is quite importante to mention that synthetic biology applications in crops does not result in organisms that are fundamentally different from traditional biotech crops.

Moreover, disease and pest resistance, nitrogen use efficiency, allowing to reduce the use of chemical fertilizers, improved quality (e.g. flavor, fibre teor and quality), photosynthetic efficiency aimed at higher crop productivity and biofortified crops to address micronutrient deficiencies are also desired outcomes aiming to build upon sustainable production.

To sum up, it is crucial to search for sound evidences when it comes to assessing the state of knowledge regarding synthetic biology. The aim to address possible damages to biodiversity and get to the right picture must be narrowed by consistent evidences and not lead to general and non-scientifically grounded arguments.

Dear Casper and other Colleagues,

Synthetic Biology is an emerging technology that should be identified as a new and emerging issue considered a new dimension of modern biotechnology, a revolution in biology advancing at accelerated rate, that impacts economies, societies and mother earth with their biodiversity and beyond on the approach of only one health. Is extremely complex taking into account the specialties and areas of knowledge involved, like life sciences and technical sciences, consequently the diversity of approaches and criteria’s.  With the current knowledge about Synbio and its regulation is difficult to predict with a high certainty the potential positives and negatives impact that’s why many criteria are elaborated on the basis of hypotheses.
“The recent developments in synthetic biology and the continued pace of development might pose challenges to the ability to understand the possible impacts on biodiversity and human health. There might be a need to consider more thoroughly the potential benefits and potential adverse effects at the ecosystem level, particularly for some developments, such as engineered gene drives.“ AHTEG Dec 2017
To contribute to this endeavour in a brief search of information and having in mind current state of knowledge (also most of them pertinent to Topic 4) I would like to share some of them, result of the search.

- “Surely, CRISPR-based technologies have empowered researchers with an unprecedented toolbox. The history of molecular biology will place CRISPR-Cas9 among the major tools that enabled breakthrough discoveries and methodological advancements in science.
CRISPR applications have already expanded our vision of genome regulation and organization in living cells across diverse biological kingdoms. In this regard, CRISPR is not only transforming molecular biology but also medicine and biotechnology.
However, the rapid development of CRISPR-based tools also brings forth a number of technical challenges along with social and ethical concerns
….a recent report documented that more than half of humans may already have pre-existing humoral and cell-mediated adaptive immune responses to Cas9 proteins
Therefore, as the CRISPR-Cas9 system moves forward into clinical trials, this factor must be taken into account
…briefly discuss current and future impacts of these tools in science, medicine, and biotechnology.
Therefore, in parallel to the current advancements, additional studies are needed to address the safety and specificity of such tools. Furthermore, sufficient considerations need to be devoted to the social and ethical implications of such technologies so that they will be accessible to all layers of society and benefit all humankind”

NATURE COMMUNICATIONS | (2018) 9:1911 | DOI: 10.1038/s41467-018-04252-2 | http://www.nature.com/naturecommunications

 Gene Drives and Environmental Concerns

“Anticipation of potential benefits of CRISPR-Cas9-enabled gene drives to human health, agriculture, and the environment is accompanied by concern over potential negative consequences to other species and ecosystems. …The fast moving nature of this field is both encouraging and concerning.. While gene-drive modified organisms hold promise for addressing difficult to solve, persistent challenges, such as the eradication of vector-borne diseases and the conservation of threatened and endangered species, these proposed applications are based on limited proof-of-concept studies. The presumed efficiency of gene-drive modified organisms may lead to calls for their release in perceived crisis situations, before there is adequate knowledge of their ecological effects, and before mitigation plans for unintended harmful consequences are in place”
Advanced Gene Editing: CRISPR-Cas9. Dec 2018
https://crsreports.congress.gov

 Social Acceptance and Ethical Concerns

“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”
“Concerns about environmental justice and who will be responsible for addressing unanticipated public health or environmental harms may also be an issue as developing countries may be primary locations for the use of gene drives.”
Advanced Gene Editing: CRISPR-Cas9. Dec 2018
https://crsreports.congress.gov

- .....  genetic changes to a population are likely to persist for a very long time, possibly permanently. This may result in far-reaching and unpredictable consequences for society and the environment
New genetic engineering techniques, like CRISPR, require further analysis in the context of agricultural ecosystems and the food system as a whole in order to properly assess their potential risks and hypothetical benefits.

Gene-edited organisms in agriculture: Risks and unexpected consequences Sept 2018
http://www.foe.org


…..future advancements in reducing the size of existing Cas proteins or the discovery of smaller Cas9 proteins is highly needed
In this powerful CRISPR application, researchers have demonstrated that a gene allele that provides parasite-resistant phenotype in mosquitos can quickly spread through the population in a non-Mendelian fashion. Such applications may greatly empower us in the war against malaria-type diseases.
However, due to the global effect of such applications, safety backups should be carefully designed and additional regulatory procedures should be considered and implemented in advance.

NATURE COMMUNICATIONS | (2018) 9:1911 | DOI: 10.1038/s41467-018-04252-2 | http://www.nature.com/naturecommunications

“Speakers discussed a variety of ways the use of genome editing tools could advance environmental health research, including new research platforms …. Speakers also commented on known limitations and bottlenecks with the use of genome editing tools.
Using the tools to do single nucleotide substitutions is still a challenge,... Their applicability for epigenome editing is still on the horizon, …. The fact that the action of genome editing needs to be validated by polymerase chain reaction sequencing is also a bottleneck
…. the need for information on delivery to different tissue types, as well as methodological input for standardization and optimization. The existence of improved gRNA design algorithms and improved prediction of off-target effects could also help environmental health research move forward”
The Promise of Genome Editing Tools to Advance Environmental Health Research: 2018
https://doi.org/10.17226/25136

I wish all a nice weekend
Warm regards,

L. Regalado

Dear moderator and Dear Forum participants,

I agree with post [#9560] which exposed views on getting the “right picture”.
As many of the on-line forum participants have already stated, one of the possible scenarios for the SynBio developments/products (i.e Gene drive-modified organisms) could be these behaving like invasive species. We already have a significant amount of information (studies) about invasive species in ecosystems, but we have limited data of possible outcomes of Ecosystem dynamics under new threats like climate change, advance of the agriculture frontiers, increasing chemical (i.e. pesticides, antibiotics) pollution, loss of biodiversity due to a complex mixture of circumstances (the previously mentioned included). Currently, we don´t know if these factors (separately, or all combined) could have an impact in the behavior of the LMO product of gene drives and/or Synthetic Biology. All these variables must be considered in the equation, the update process of risk assessment of the new developments of Synthetic Biology, and even then, I personally think that “the right picture” will be evolving from the information we can produce and obtain.

Regards,

Emmanuel González-Ortega

Dear Forum participants,

I will address both topics 3 and 4 with this post. The three guiding points and questions from the moderator in topic 3 are helpful to keep in mind for all discussions on this topic. Indeed there are mixed views on what the “right picture” is in these discussions, and an influx of information that may or may not contribute to this. In an attempt to provide relevant information – being information that informs and progresses the discussion – the GIC has taken the approach of looking back at what has been done (technological development, the resulting organisms, the accumulated scientific knowledge base, and the decades of regulatory expertise), the current status of the science under discussion (is it a concept? a proof-of-concept? what is a realistic application? are there significant technical challenges to overcome?), and how realistically foreseeable is deployment of the application, e.g. in the next 5, 10 or 20 years. Thus, the idea of “technology readiness” proposed in topic 1 (Geoff Turner #9449) resonates strongly.

Coming from a commercial R&D and regulatory perspective, I think of “new development” as an application that has advanced beyond initial research stage into the development process. This contrasts with the early stage/fundamental/proof-of-concept research that dominates these discussions, along with speculation of all of the possible applications and associated positive/negative effects. Certainly, this is promoted by the claims made in the scientific literature itself about the possibilities, and this is normal practice – extrapolation of all potential applications for new concepts drives successful research funding, and this needs to be understood in that context. Similarly, so do claims made in patents. It was evident in topic 1 that patent claims are being used to identify “new developments”. It is normal practice for patent claims to be drafted in order to provide a broad scope of protection in the use of the invention (e.g. a technology). These reflect the possibilities for which the invention could be applied in a commercial setting, but it is misleading to state that they are “new developments”, actual applications in development, or intended commercial activities, since most patented inventions (e.g. more than 95% in the US) are never commercialized (see https://nsf.gov/statistics/2018/nsb20181/report/sections/invention-knowledge-transfer-and-innovation/invention-united-states-and-comparative-global-trends).

As pointed out by our moderator, topic 3 is intended to cover the effects resulting from the “new developments” listed in topic 1, but this information was largely provided in topic 1. Also, as pointed out by others, the potential benefits and potential adverse effects (2015) and evidence (2017) for these have been covered previously in online discussions, information submissions and AHTEGs. In our 2017 (https://bch.cbd.int/database/record.shtml?documentid=112053) and 2019 (https://bch.cbd.int/database/record.shtml?documentid=114285) submissions, the GIC reviewed the substantial body of literature providing credible evidence of the impacts of existing products of biotechnology, with many actual (not potential) environmental and socio-economic benefits demonstrated since the commercialization of LM crops in the 1990s. I agree with others who have pointed to the existence of relevant precedent (e.g. #9500, #9529, #9544, #9566). For LM crops, the concerns raised decades ago are being echoed now for organisms containing engineered gene drives, and similar proposals are being made about the need for a precautionary step-wise approach to field releases and risk management (see the GIC’s review of this in their 2019 submission on risk assessment, to be made available here: http://bch.cbd.int/onlineconferences/submissions.shtml).

Reading this online discussion creates the impression that synthetic biology presents more potential negative consequences than positive, but this is not reflected by past experience, and I appreciate the reminder (#9570) that it is the potential benefits that drives the majority of new developments. It is worth noting here the benefits of LM crops that have been realized: improved soil fertility, reduced chemical inputs, reduced fossil fuel use, reduced impacts on non-target organisms, area-wide pest suppression, decreased CO2 emissions, increased efficiency of water use, and higher yields (see the collection of publications at: http://biotechbenefits.croplife.org/impact_areas/environmental-benefits). The benefits of proposed “new” applications in crops include those listed above, as well as disease and pest resistance, nitrogen use efficiency (reduced fertilizer use), improved quality (e.g. flavor, fiber quality), and improved processing characteristics. Recent examples include photosynthetic efficiency work aimed at higher crop yields (South et al 2019), and biofortified crops to address micronutrient deficiencies (Garg et al 2018; Paul et al 2018; De Steur et al 2017).

Genome editing applications in agricultural crops have featured in these discussions, and we do not believe that these belong in synthetic biology discussions. Genome editing represents a broad category of enabling tools that can be applied to achieve various outcomes in plants, with some outcomes comparable to existing biotech (LMO/GMO) plants, and others comparable to plants developed with conventional breeding tools. Therefore, current and foreseeable applications of genome editing in plant breeding do not result in crops that are fundamentally different from those currently commercialized. We also emphasize that where the product is an LMO, it is within the scope of the existing regulatory mechanisms that apply to “traditional” LM crops, and its potential impacts will be assessed on a case-by-case basis consistent with the risk assessment principles of Annex III of the Cartagena Protocol.

References cited:
South PF, Cavanagh AP, Liu HW, Ort DR (2019) Synthetic glycolate metabolism pathways stimulate crop growth and productivity in the field. Science 363: DOI: 10.1126/science.aat9077 

Garg M, Sharma N, Sharma S, Kapoor P, Kumar A, Chunduri V, Arora P (2018) Biofortified crops generated by breeding, agronomy and transgenic approaches are improving the lives of millions of people around the world. Frontiers in Nutrition DOI: 10.3389/fnut.2018.00012.

De Steur H, Demont M, Gellynck X, Stein AJ (2017) The social and economic impact of biofortification through genetic modification. Current Opinion in Biotechnology 44: 161-168.

Paul J-Y, Harding R, Tushemereirwe W, Dale J (2018) Banana21: From gene discovery to deregulated golden bananas. Frontiers in Plant Science 9: DOI: 10.3389/fpls.2018.00558.

Dear Colleagues

With regards to potential synthetic biology applications for conservation and environmental management purposes I would like to propose that it would be informative to separate out potential risks that would be unique to synthetic biology approaches being applied, from those that would be incurred irrespective of the mode of management being employed.

To take the example of pest control, potential knock-on ecological effects of reducing pest population numbers would be incurred irrespective of the approach used being a synthetic biology one or, for example, the broad-scale application of toxins and chemicals.

Kind regards, Dan Tompkins.

Dear colleagues,
First of all I would like to thank Caper to facilitate this multilayered discussion.

I would like to echo Jim (#9508) and Helmut (#9540) who have suggested that we build on the compilation on this subject put together by the AHTEG at its Meeting in 2015, but also in 2017. Given the many new developments that we have discussed under topic 1, the AHTEC could help to further structure and analyses this comprehensive information by given weight to the most important developments with respect to their impact on the goals of the convention.

With respect to the suggestions by Rodrigo (#9561) to include the concepts of “damage” also in this analysis, I think that it is important to bear in mind that the very concept of the horizon scanning is to spot developments at an early timepoint to give parties and regulators the necessary time to get prepared. The concept of “damage” from the Cartagena context does not seem to be a suitable tool in this process, since damage must already be measurable. A horizon scanning would have failed, if it would only spot the developments, when the damage is already measurable. Let me give you an example: gene drives are by concept a technology that is in principal able to eradicate species. They have however not been released yet and therefore potential damage to let’s say biodiversity is not measurable. But we cannot wait to the fist measurements of potential damage, because as Noble et al. have shown (DOI: 10.7554/elife.33423) “current first-generation CRISPR-based gene drive systems for population alteration are capable of far-reaching—perhaps, for species distributed worldwide, global—spread, even for very small releases.” They have done so on the basis of mathematical models, and I think that such approaches could be increasingly important in the evaluation of synthetic biology applications.

Many applications intended for the release into the environment are at the proof of concept state, as e.g. seen for synthetic gene drives. As no synthetic gene drive is ready for deployment, all approaches to estimate impacts remain theoretical at many levels. For gene drives knowledge is first accumulated on the level of technological progress (i.e. the development of the technique). As a second step developers and regulators are concerned with the behavior of the gene drive construct in nature. Data are based on theoretical modeling approaches, due to lack of field experiments using synthetic gene drives.

To reflect the current state of knowledge one has to clarify, which questions remain open and to identify the knowledge gaps when attempting to perform risk and impact assessments.
Exemplary for gene drives those questions could include:

• What is the level of genetic, behavioral and mating diversity in the wild and how does it influence the gene drive?
• What are the effects on the biodiversity in the ecosystem where the gene drive is released? Which other ecosystems are affected (directly by invasion or indirectly)?
• Do we have enough knowledge about the ecology and the specific roles of the target organism in the ecosystem? Are we able to characterize the complex relationship between ecosystems and gene drive organisms?
• Do we have sufficient models to extrapolate effects (which can be species wide in the most extreme case) from the collected data?
• Are risk assessment guidelines sufficiently amended and operational (including limits of concern) to be able to reflect the increased demands posed by synthetic gene drives?

In addition Nina (#9560) has correctly pointed out that science is at the beginning of the understanding, predicting and controlling such a complex phenomena as the biodiversity dynamics. If we consider the application to modify wildlife, where scientific experience is in its infancy, and the shift in strategies that may lead to common goods, it becomes clear that mere risk assessment comes to its limit. To agree on thresholds, necessities,  acceptable  uncertainties  and common goals, a wider societal perspective is needed. We should therefore discus technology assessment approach that goes beyond mere risk assessment. On a basic level, this approach could discuss the appropriateness of the technique in comparison with other means to achieve the goal. On a wider scope, it could incorporate a certain appraisal of social, economic and cultural impacts that are no part of the pure risk assessment. This is again an area of limited knowledge.

All the best,
Margret

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). 

I wish to agree with Margret’s recent post [9577] when she says that quantitative mathematical or computer modelling are likely to be useful in evaluating synthetic biology applications. However, I believe regulators will often be able to draw on more than just mathematical models, as often there will be useful precedents that do not involve synthetic biology. For the specific example of gene drives that suppress a population, and the ecological effects following from that, it will often be possible to get relevant information on the ecological impacts of suppressing the target population by others means. For example, for the specific scenario of using a (localisable) gene drive to eliminate an invasive rodent from an oceanic island, it will be possible to refer to the ecological impacts of eliminations that have occurred by other means (e.g., dumping large quantities of poison). My understanding is that these impacts are typically positive (and, indeed, the whole rationale for the intervention). Similarly, for the specific scenario of using gene drive to reduce populations of malaria-transmitting Anopheles gambiae mosquitoes in sub-Saharan Africa, it will be possible to refer to the ecological impacts of reductions caused by chemical control (insecticide-treated bed nets, indoor residual spraying of insecticides, and larviciding). In some regions in East Africa these interventions have made An. gambiae, previously highly abundant, now difficult to find. I am not aware of any reports of negative ecological impacts as a result. In both scenarios data from chemical control ought to be relevant and useful in assessing proposals for genetic control.

Kind regards,

Austin Burt

It is necessary to consider the potential positive and potential negative impacts of synthetic biology, taking account SB aims to construct novel biological entities and to redesign existing ones, novel organisms would present a particular challenge because of the lack of prior experience   (http://www.oecd.org/sti/emerging-tech/45144066.pdf) and CRISPR/Cas9 (Jinek et al.2012 In: https://www.tandfonline.com/doi/pdf/10.1080/23299460.2017.1415585?needAccess=true&). So, we need to evaluate case by case and monitoring in the long term at ecosystems structure and functions and wild populations structure where SB is developing on the field. We need to regard if SB living organisms have positives or negatives impacts in ecosystems, communities and wild populations on its conservation, sustainable use or sharing benefits to local communities to enhance biological diversity conservation and decrease or stop biodiversity lost.

Dr. Marina Rosales Benites de Franco
Universidad Nacional Federico Villarreal

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 colleagues,

Thank you all for this discussion and thank you Casper, for your questions and guidance.

I would like to address two points mainly, namely the meaning of “right picture” and secondly the state of knowledge or lack of knowledge regarding potential positive and negative environmental impacts of gene drives.

It is difficult to keep all the different topics apart and this reflection and input will also be in large part applicable for Topic 4 “Possible impacts of synthetic biology applications that are in early stages of research and development”, as many currently debated gene drive systems and applications fit the criterium of “early stages”, or may even be still at a conceptual, a hypothetical/theoretical stage.

I would also like to offer, in a separate submission, a number of references that I believe are relevant to the discussion of topic 3 and that have not yet been included in the helpful lists and individual references posted by some of you, for which I am thankful.


As Casper pointed out, there are mixed views on what is understood to be a “right picture” . Jim suggested it to mean “getting the right balance” [#9508], others were not sure that we can have a “right picture” at this stage due to lack of sufficient data, especially long-term data [#9557], which is a point that was also made in a different way by Nina Voronova [#9560]. The latter contribution actually helped me understand what “right picture” means to me, which would be something like a “full picture” (i.e. meaning not just a partial one).

The understanding and acknowledgment that there is ‘lack of knowledge’ or ‘missing knowledge’ is for me part of that right picture. If one knows which purpose the/a picture has to serve, then one can agree what needs to be in it, which components belong in there, which aspects, which facets. Is it a picture for a specific scenario, or does it need to cover all of them, and which scenarios would that be (ie do we have that list of scenarios)? So, the questions in a way are part of the picture, as they allow one to either fill in a piece with data, observation, evidence, modelling, or simply leaves a blank.

A “full picture” means do we have the whole spectrum in front of us of the knowledge that is required, and in the context of the CBD that includes all types of knowledge. So lack of knowledge, if that is identified as the current status of knowledge, is part of the “right picture” or the “full” picture. The fact that there are gaps, blanks or pencil notes is just letting us know that there are limits to the current knowledge relevant to the issue at hand.

With regards to Gene Drives and Gene Drive Organims (GDOs) currently under development and their potential positive and negative environmental impacts - a “right picture” would for example urge to look at all possible scenarios that could arise and to guide to the relevant data, evidence and knowledge required and to then check if it is available.

If for example, we take the case of a homing CRISPR/Cas based gene drive designed for suppression or elimination of a population or species: then we can look at scenarios where the GDO is released and hardly any drive happens all the way to where the drive runs all the way, with 100 % extinction. As it cannot be predicted how the GDO will actually perform in real life, under natural conditions within a wild population, all the different scenarios along the line from no drive to full drive will need to be contemplated, understood and assessed for available data and knowledge. Questions may want to cover understanding the implications of the presence of mosaic populations (LMO without drive, GDO, wild), separate populations, elimination and then reinvasion of niche by the same species (and when), reinvasion by very close relatives, invasion by others). And what are the health risks? And what about having an active CRISPR/Cas 9 within the LMO population though with a resistant target site? There is are different papers looking at all these different aspects, but there is no picture as yet. Nor the frame for it.

Gene drives deserve full attention with full recognition of the complexities involved both at ecosystem level, as illustrated for example in [#9560], and on technical, behavioural and system levels, as put to us by Helmut [#9540]. I am grateful for his very helpful input and would like to pick up two threads there.

Regarding resistance: Nikolay [#9534] has already introduced Kyrou et al.’s experiments – who followed closely the advice in Burt 2003 to use well conserved and vital genes to minimise or prevent resistance. This though increases in turn the likelihood that CRISPR-based homing drive may also work in closely related species once it gets there, i.e. via hybridisation - a point made by Helmut and as is the potential with Kyrou’s drive within the A. gambiae complex. This means that the one step forward to avoid the otherwise unavoidable emergence of resistance, namely by using conserved and vital genes, is opening the door wider for a yet different kind of risk.

There is though a different form of resistance that may need to be taken into consideration, as pointed out by Lindholm et al. (2016), who reports:

“Sexual Selection against Driver-Carrying Individuals: Male and female mating behaviour are predicted to influence driver dynamics. The costs associated with drive create a benefit to avoiding mating with individuals carrying a driver, and thus preferences against driver carriers are expected to evolve [63]. In stalk-eyed flies (Teleopsis dalmanni), females prefer to mate with males with larger eyespans, and driver-carrying males tend to have smaller eyespans [64,65]. In some house mouse populations, females carrying the t haplotype discriminate against driver males in choice tests, although wild-type females show no preference [66,67]. However, as recombination is expected to break linkage between drive elements and traits that allow mate choice [63], with undetectable drivers predicted to rapidly outcompete detectable forms, premating discrimination against driver males might be uncommon [6]. Alternatively, as many sperm killers significantly reduce sperm numbers, females could potentially avoid drivers by preferentially discarding sperm from males transferring small ejaculates, as hinted by a study in D. simulans [68]. The production of driver-carrying progeny can also be avoided through sperm competition when females mate with multiple males, assuming driver- carrying males are poor sperm competitors [69]. Both theoretical models [51,60,70] and empirical studies [54,55,61,71–73] support the idea that gamete competition can reduce driver frequencies and limit the spread of male drivers under some conditions (see [51]). Indeed, the presence of drive elements can select for and lead to an increase in female mating frequency. If female mating rates are density-dependent [73], this could make drivers rare in denser populations.”

The implications of altered mating behaviour or not anticipated mating behaviour (e.g. lab-rodents under lab-conditions have a different mating behaviour than rodents in the wild - see Leitschuh et al. 2018) deem important both for modelling purposes as well as for understanding of risks. Understanding migration behaviour is equally crucial for modelling (Dhole et al. 2018).  Similar questions have been raised by Margret Engelhard [#9577].

I have one last open question: Would it not be meaningful to also understand which data is necessary and which questions to ask and what to consider for performing a robust potential environmental benefit assessment?


References:

Dhole S, Vella MR, Lloyd AL, Gould F. 2018. Invasion and migration of spatially self-limiting gene drives: A comparative analysis. Evol Appl 11: 794-808.
Leitschuh CM, Kanavy D, Backus GA, Valdez RX, Serr M, Pitts EA, Threadgill D, Godwin J. 2018. Developing gene drive technologies to eradicate invasive rodents from islands. Journal of Responsible Innovation 5: S121-S138.
Lindholm AK, Dyer KA, Firman RC, Fishman L, Forstmeier W, Holman L, Johannesson H, Knief U, Kokko H, Larracuente AM et al. 2016. The Ecology and Evolutionary Dynamics of Meiotic Drive. Trends Ecol Evol 31: 315-326.

I will post some further references later.

With kind regards,

Ricarda Steinbrecher
Federation of German Scientists

Dear Forum participants,

I find Piet’s summary and comments of the discussions very helpful [#9589], as well as the reminders to separate technology applied from the result [#9572] [#9589 “… 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.”]. At the current state of knowledge, in my view, risks and impacts on environment and diversity have to be assessed on a case-by-case basis. I agree to the suggestion [#9573] that identifying risks and impacts unique to applications based on synthetic biology concepts would be informative to further discussions.

Regards,
Anke

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.)
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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