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

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

1) If possible, for each of the trends identified by the AHTEG provide the following information:

a) What are some examples of near-future applications? And what is the timeframe for release of the applications, either for research or commercialization (0 to 5 years; 5 to 10 years; 10+ years)?

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

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

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

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

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

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

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

Sincere regards,
Dr. Martin Cannell

Hello, My name is Adanna Mgbojikwe-Loto.I work with the National Biosafety Management Agency, Nigeria as a regulatory scientist with a background in Biochemistry. I have garnered experience in risk assessment and regulations for GMOs in relation to confined field trials and commercial releases.

An example of near-future applications is the work by Akos Nyerges of Harvard Medical School and his team which provides the basis for a general strategy to make any organism safely resistant to all natural viruses and prevent genetic information flow into and out of GMOs.

These researchers have modified a strain of Escherichia coli bacteria to be immune to natural viral infections while also minimizing the potential for the bacteria or their modified genes to escape into the wild.

In previous work by a group from the University of Cambridge (2022), the method involved genetically reprogramming E. coli to make all their life-sustaining proteins from 61 sets of codons, instead of the naturally occurring 64. The idea was that viruses wouldn’t be able to hijack the cells because they couldn’t replicate without the missing codons. This was unsuccessful as it turns out that some viruses could still infect the modified bacteria.

The work by the team at Harvard Medical School built on this by adding new 'trickster tRNAs' to the codon of the E.Coli which when they read TCG or TCA codons added leucine instead of serine resulting in misfolded, non-functional viral proteins, preventing the escape of synthetic genetic information by engineered reliance on serine codons to produce leucine-requiring proteins.

This research work was published in March 2023 (https://www.nature.com/articles/s41586-023-05824-z). There's possible exploration into codon reprogramming as a tool for coaxing bacteria to produce medically useful synthetic materials that would otherwise require expensive chemistry by Nyerges but no timeframe was stated for further research.

Within Nigeria, the National Biosafety Management Agency (NBMA) has developed Guidelines on Genome Editing and has also begun work on regulations for SynBio but hasn't received any applications for research related to trends identified by ATHEG.

Hello, my name is Owain Edwards and I lead a research group at CSIRO in Australia with a focus on synthetic biology technologies that aim to solve environmental problems, including biodiversity/conservation.   In terms of near-future environmental applications, I would expect synbio-based remediation or waste-recycling technologies to be the first to market:  Engineered microbes within a 5 year time frame, and engineered plants and animals possibly within a 10 year time frame.  Genetic pest control technologies (not just gene drives) I would expect to be field tested within 5-10 years.   Of the synbio approaches aiming to improve the resilience of threatened species, few are likely to deliver within a 10 year time frame - possibly with the exception of those aiming to provide disease resistance. 

Regards,
Dr Owain Edwards

I am Dagmawit Chombe working as senior researcher in Bio and Emerging Technology Institute I have specialized in plant molecular genetics and systematics. I also work as national biosafety advisory committee advising the government on issues of Biosafety.

Ethiopia has started to develop guideline for genome edited technology and guideline for food and feed which is at the last stage of approval. The rational for developing guideline for deregulating genome editing technologies is due to the start of same collaborative research work on genome editing of striga resistance sorghum, reduced lodging and grain shatter in tef, oil from Brassica carinata and so on. The application of synthetic biology technologies has not started yet, however, there are initiatives and various communications between scientists on forum of Genome Editing organized in collaboration with The Bio and Emerging Technology institute and the Center of Excellence for Science Technology and Innovation (CoE STI) of the African Union Development Agency-NEPAD (AUDA-NEPAD)

Hello, my name is Prof Nicolas BARRO, I am former Director General of National Biosafety agency of Burkina Faso. I am now a director of foodborne pathogen surveillance laboratory and Advisor of Minister of High education
The synthetic biology   technologies could be very interesting if we exploit some natural events. Our laboratory works on identification of some naturel genetic and phenotypic phenomenons, which can be clarified and copied artificially and serving as basic construction of synbio.
However they are a real need of capacity building on this new technology (origin, biochemical, genetic aspect, cause, potential applications, etc.).

Hello, my name is Galina Mozgova. I am geneticist, Head of the National Coordination Biosafety Centre of the Institute of Genetics and Cytology, member of the Expert Council on LMO safety.
With regard to the new practical applications, we expect fairly quick entry into the markets of countries of agricultural crops developed by the methods of genome editing (CRISPR-Cas and others) based on the fact that a lot of scientific publications on genomic editing, including nucleotide insertions, have been published in recent years, specifically for genes that control economically valuable traits, which means that these are practice-oriented studies. In 2021, we tried to search for gene sequences of the rapeseed that are responsible for the synthesis of unsaturated fatty acids, and did not find those for which research editing work had not been carried out. I do not present articles here, because there are a lot of them and they are all available on the Internet. Screening can be done fairly quickly for the gene and crop of interest.
The fact that interest in genome editing technologies does not weaken, says the constant appearance of articles on the sophistication of methods. The reviews on the sophistication of techniques are presented in the Literature Sources of the CBD Technical Series 100 Synthetic Biology (2022). In 2022 Hu et al. introduce a new member into the work force - a CRISPR RNA-guided protease, the new CRISPR-Cas system with on-off switch cuts proteins
https://www.science.org/doi/10.1126/science.add5064
https://www.tudelft.nl/en/2022/tnw/new-crispr-cas-system-with-on-off-switch-cuts-proteins
There is also an interest in development and incorporation of artificial intelligence/ machine learning in the design of experiments. For very promising from practical point of view object, microscopic algae, in 2022 a review article on sophistication of machine-learning method published:
Bin Long [et al] Machine learning-informed and synthetic biology-enabled semi-continuous algal cultivation to unleash renewable fuel productivity https://www.nature.com/articles/s41467-021-27665-y

In addition, there is an interest in changes in not only the nuclear genome but the other cytoplasmic organelles. There are a number of articles on genome editing or engineering of plastome, but it seems that most of developments are on the research stage because of the complexity of the object.
In any case there is a trend and interest in increasing sophistication of methods and development of artificial intelligence for design of experiment of microscopic algae and other microorganisms. Emerging synbio tools for engineering for example described in these reviews:
https://www.frontiersin.org/articles/10.3389/fpls.2021.708370/full;
https://www.frontiersin.org/articles/10.3389/fbioe.2020.00914/full
http://uu.diva-portal.org/smash/get/diva2:1623190/FULLTEXT01.pdf
Design–build–test of a novel synthetic ‘mini-synplastome’ https://onlinelibrary.wiley.com/doi/full/10.1111/pbi.13717.
It is difficult to predict how quickly such research will move into practice based on articles. Perhaps one of the search directions can also be patents and partner websites, such as OECD, ISAAA, FAO GM-Platform, etc., as well as a search for news from scientific institutions about ongoing scientific projects.

Best regards,
Galina Mozgova

Hello everybody, my name is Christoph Then and I am a member of ENSSER (The European Network of Scientists for Social and Environmental Responsibility) and representing Testbiotech (http://www.testbiotch.org) in this discussion. Testbiotech has been conducting a project in horizon scanning https://fachstelle-gentechnik-umwelt.de/en/home/ on new genomic techniques that is also relevant for Synbio applications. We compiled recent information in a backgrounder for this forum https://www.testbiotech.org/node/3036.

To our opinion, it will be difficult to predict the organisms that may or may not enter the market in the near future. There is a lot of research going on (see our backgrounder) and some producers may consider their products ready to go to the market, although, from the perspective of the precautionary principle, this still would require much more consideration and risk assessment. In the end, we will need regulatory systems that provide sufficient oversight and informed decision making to answer these questions.

I agree with the assumption underlying Dr Dr Mozgova’s and Dr Edward’s contributions, that we can predict the applications that may or may not come to potential realisation in the near future. There are clear signals of advancement along the developmental pathway, from fundamental research, to translational research, to applied research, to decisions to support application or not, that can be used to place developments within time horizons to potential application.

On the behalf of IPLCs, I would like to response on TOPIC 1: Question 1a, and am referring the near-future application of synthetic biology either research and commercialization of the products.  Evidence information, reality, reliability, accessibility, governance and marketing of the outcomes.

The process seems confined frame and cost for implications another side the major societies are beyond from the innovations with unknown, unexpected or adverse impacts in biological world. If it appears,  it is unclear to solve and responsible regarding the respective approaches that harm in the systems.

Minimizes potential inequality, risks and establish, maintain regulations, participatory, cultural appropriate are important.

Kamal Kumar Rai
IPLC

Greetings! Leocris Batucan, a fellow for the National Committee on Biosafety of the Philippines.

In terms of near-future applications and highly likely for commercialization is the use of synthetic biology for the development of petrochemical precursors and other industrial applications.

Hello...Alexandre Nepomuceno from the Brazilian Agricultural Research Corporation - EMBRAPA, and member of the Brazilian Biosafety commission. We are moving from a Fossil precursors economy to a Chemical Green Precursors economy. Agricultural raw materials will be the backbone production of fuels, bioplastics, tires, etc, etc. Synthetic biology is already playing a role on that. For example, the use of sugarcane fermentation to convert basic plant sugars into  bioidentical molecules to the molecules used as ingredients to produce everyday products. Soybean plants also have been modified to change/improve oil quality thus it could be used as a biofuel for planes or other machines. We will see this products in the market soon, maybe 5 years, maybe 10-20 years from now...but we will see.

Hello everybody in this forum.
I’m Emmanuel González-Ortega, I am Biotechnology Research-professor at the Universidad Autónoma Metropolitana Xochimilco, in Mexico City. I’m also a member of the Unión de Científicos Comprometidos con la Sociedad y la Naturaleza de América Latina (UCCSNAL - uccnsal.org) and representing CECCAM (Centro de Estudios para el Cambio en el Campo Mexicano) -an independent research center studying issues related to agriculture in Mexico- in this forum.

Although previous comments in the forum argue that the prediction of the release timeframe of applications and/or products of Synbio, either for research, commerce, (I would add for conservation) is possible (it is stated: 5-10,20 years), I coincide with Dr. C. Then that, from a precautionary perspective, it is difficult to estimate the time for these developments to be released.
In addition, I would like to point out that it has to be considered that the expectatives, interests, rights, and needs of IPLCs not necessarily and often does not coincide and converge with the mainstream objectives of these SynBio developments (all three categories previously mentioned considered). Moreover, the Nagoya Protocol observes the fair and equitable sharing of benefits from the access and utilization of genetic resources, so the release of Synbio developments without the assessment of potential negative impacts to ecosystems, societies and economies from these developments could generate a point of no return, since these SynBio LMO biotechnologies are, in some cases, designed to be specifically released to the environment, and could provoke impacts far beyond the expected or considered in many orders or dimensions, i.e.: allelic (acting at population genetics), ecologically (changing populations of non-target species), socio economically (abruptly ending an essential economic activity of a community or society).

As an example, a recent report by Friends of the Earth Austria, Friends of the Earth Europe, Corporate Europe Observatory, Arche Noah, IG Saatgut – Interessengemeinschaft für gentechnikfreie Saatgutarbeit and Arbeiterkammer Wien assessed the current-future implications for farmers, breeders and the food chain in general, of the patents applications or patents granted to genetically modified organisms (seeds) produced through emerging biotechnologies  (https://friendsoftheearth.eu/press-release/how-biotech-giants-use-patents-new-gmos-to-control-future-of-food/ ).

Hello,

Dr. Tiffany Kosch, University of Melbourne, Australia. We are currently investigating targeted genetic intervention methods to increase resistance to chytridiomycosis in Australian frogs. At the moment, most of our work focuses on understanding the genetic basis of resistance in species such as corroboree frogs, but we plan to start attempting to increase it in the next few years. This will involve trialing approaches such as genomic selection, gene editing, and transgenesis. We expect our project to be very long-term, meaning that it will be at least 15-20 years before we might consider doing trial releases into the wild. Luckily, our two focal species have well-funded conservation breeding programs to keep them from going extinct while we test these approaches.

Hello everyone,

Safendrri Ragamustari from the Indonesian National Research and Innovation Agency. It's wonderful to hear the many ideas and thoughts on the future of synthetic biology.

Due to synthetic biology's nuanced definition, I would like to add that there are already many synthetic biology-based products that have been put out in the market or at a very advanced stages, particularly in the savory and flavor industry, where certain metabolites / chemical compounds (such as vanillin) are produced without traditional vanilla plantations.

In the next 5-10 years, with new metabolic pathways being elucidated, I think we will see more natural products be produced synthetically, replacing traditional systems. The impacts of the process of converting to synthetic systems for production needs to be assessed from the economic, social, cultural, political, technological, environmental, and legal aspects.

Best regards,
Fendrri

Greetings/kia ora
I have already introduced myself to the forum under question 2. I am a molecular biologist/genetic engineer at a university.

Like Mr Then [#2607] I think it is difficult to estimate timeframes, especially for applications such as described by Mr González-Ortega [#2626] that are released living organisms or intended to be used outside of containment. We often hear about new things and they are often promoted as being just around the corner. Either unanticipated technical issues or issues of business can confound timelines. This also works sometimes to accelerate them.

Having said that, we have done some work in an area that has characteristics that might allow it to begin commercialisation at the low to medium range (ie, <10 years). The reason I say this is because it is not solely a ‘biotechnology’, but a combination of biotechnology and chemical technology and ad hoc changes to regulations in some countries.

[We discuss how changes to regulation made alongside rapid changes in biotechnology and chemistry can alter estimations of risk here: https://doi.org/10.3389/fgeed.2022.1064103]

The biochemical stability of genome editors, eg CRISPR/Cas nucleoprotein complexes, and RNA modifications, eg as can be used to make double-stranded RNA to cause RNA interference, in the last 10-15 years is being combined with the chemistry that makes the transport of those biological reagents into cells far more efficient. That allows for scale up and the potential to modify traits using these biological reagents outside of contained laboratories. Such uses are referred to in the academic literature and patent literature by different names. Some of the terms are “topical”, “spray on” (but they do not need to be only sprays) “contact” and “environmental genetic engineering”.

[We discuss this topic in depth here https://doi.org/10.1016/j.bsheal.2019.09.003].

What could limit the scale advantages achieved by being used on demand outdoors is regulation that requires all exposed organisms to be assessed prior to their introduction into the environment. With some countries defining some uses of genome editing or dsRNA out of regulations, or out of legislative scope entirely, the commercial scale advantage can be realised but could be a trade-off with safety and other relevant concerns.

If we use the patent term as a guide to how close such products might be to commercialisation, then they are less than 10 years away (assuming that a patent has a 20 year life). We have surveyed the patent literature and provide examples both in https://doi.org/10.1016/j.bsheal.2019.09.003 and in https://doi.org/10.1016/j.envint.2019.05.050.

Siguna Mueller has also evaluated the synergy of changes in biotechnology/chemistry and developments in computer science that have implications for horizon scanning. This is also mentioned by Dr Mozgova [#2602]. Siguna makes the point that countries choosing to allow some products of modern biotechnology to be un-notified to authorities increases the ‘cover’ for those who might use these same techniques to do purposeful harm. Because Siguna is in this forum, I’ll not say more about this, except to point to some of her publications.
https://doi.org/10.1016/j.bsheal.2020.09.007 https://doi.org/10.3389/fbioe.2019.00121

Because outdoor use will be attractive for making pesticides using genome editors or dsRNA, this product line will slot into the agrochemical industry that already dominates in the distribution of GM plants. That usage therefore could become commercialized and distributed on a broad scale faster than many others.

Another attractive use of these products is the ability to make them act as herbicides to older varieties of GMOs (or a competitors GM variety). This is attractive when herbicide resistant crop plants become weeds in other settings, but also attractive as a means to ensure that farmers don't save seeds or make it more difficult to switch between seed suppliers.

If more regulators opt to place pesticidal uses within chemical regulation rather than GMO regulation, then the use of nucleic acids (DNA, RNA) and nucleases (eg Cas) as active ingredients could cause these products to receive a much more limited analysis based on the chemical components, where many regulators already define the components as safe. Their ability to cause changes in surviving target organisms, or in exposed non-target organisms, may not be evaluated as per GMO regulations.

Therefore, through either limited de-regulation or re-definition of regulations, outdoor genetic engineering may come to commercial reality in the middle timeframe.

With best wishes
Jack

Dear distinguished colleagues, my name is Dr Eva Sirinathsinghji, I am a biosafety research associate/consultant at Third World Network (TWN), with background training in molecular neurogenetics. I served on the 2019 AHTEG on risk assessment and management that focussed on LMOs containing engineered gene drives and LM fish. I look forward to learning and discussing these critical issues. I’m structuring my comments around the trends identified by the 2019 AHTEG.

Trend 1: Increased field testing of organisms, components and products derived from new developments in synthetic biology

LMO viruses  (also applicable to trend 2 identified by the AHTEG):
Three such spreadable ‘vaccine’ virus projects appear to be already underway, including a field trial approval in 2019 in the US for the release of a living modified raccoon poxvirus to be used in bats to combat white nose syndrome. This trial appears to have been approved (APHIS, 2019, https://www.regulations.gov/docket/APHIS-2019-0043/document). Two further projects are being developed by US and UK research institutions, with the intention to release GM viruses in South American and West African regions, targeting the rabies virus in bats, and the Lassa fever virus in rodents, respectively. https://doi.org/10.1126/science.abo1980 https://www.preemptproject.org/about
Virus-based gene drive applications for human therapies appear to have also been recently approved for trials in at-risk people, with potential for this type of technology to be also e applied to other applications with potential impact on biodiversity. https://grantome.com/grant/NIH/DP1-DA051144-01

Trend 2: increasing development of technologies that genetically modify organisms directly in the field (also relevant to Trend 3 with regard to increasing shifts of applications for environmental, conservation and health uses). 

Microbes:
In addition to LMO virus applications as vaccines, LMO viruses are also being developed for Horizontal Environmental Genetic Alteration Agents (HEGAAs), with recent identification of plant viruses in various global regions that are capable of infecting a variety of crop species including wheat and sugarcane (Chung et al., 2021; Ilbağı et al., 2022 https://doi.org/10.1111/pbi.13585 and https://doi.org/10.1128/mra.00745-22 ).

A recent publication (Rubin et al., 2021) has reported the development of ‘species-specific editing’ that “provides the first broadly applicable strategy for organism- and locus-specific genetic manipulation within a microbial community, hinting at new emergent properties of member organisms and methods for controlling microorganisms within their native environments.” Moreover, this work is being envisaged for a variety of applications inclusive of “agricultural, industrial, and health-relevant microbiomes”. https://doi.org/10.1038/s41564-021-01014-7

There is a recent development of a living modified plasmodium malarial parasite (Buchman et al., 2021). It remains unclear how such an application may be administered, if for example it is envisaged for environmental release or individual treatment e.g. as a vaccine. https://doi.org/10.1126/scitranslmed.abn9709

Gene drive mosquitoes:
Increased drive efficiency has been recently developed in Aedes aegyptii mosquitoes that may be relevant to potential future trial releases: https://doi.org/10.1038/s41467-023-36029-7

Negative developments are also vital to any horizon scanning process, especially when weighing up the potential costs and benefits of a technology against other existing or developing alternatives. One of the lead candidates for first field release is the double-sex Anopheles gambiae self-sustaining gene drive being developed. However, it was recently reported to the WHO that this product is now suffering from mutations within the transgenic components that have “compromised the genetic stability of the strain” (World Health Organisation, 2022 https://www.who.int/publications-detail-redirect/9789240066021). Information on the technical developments, including challenges, would greatly assist processes such as this in being able to anticipate timeframes for potential releases.

Trend 4.  Increasing sophistication of methods, including, for example, new genome editing techniques, more complex metabolic engineering, the recoding of genomes, and the use of artificial intelligence/machine learning for the redesign of biological systems

Novel delivery methods are being developed that may allow for direct genetic modification of species while circumventing technical bottlenecks. For example, viruses are being developed to deliver genome editing machinery to crops following leaf inoculation, resulting in heritable editing (T. Li et al., 2021; Liu et al., 2023 https://doi.org/10.1016/j.molp.2021.07.010 and https://doi.org/10.1038/s41477-020-0704-5). Recent developments to widen CRISPR delivery also include the use of grafting to deliver editing machinery from rootstocks to scions (Yang et al., 2023 https://doi.org/10.1038/s41587-022-01585-8). The use of phage viruses is also underway to modify bacteria https://today.ucsd.edu/story/therapeutic-potential-of-bizarre-jumbo-viruses-tapped-for-10m-hhmi-emerging-pathogens-project

CRISPR applications are also being broadened in mosquitoes, with for example the use of CRISPR to alter gene expression levels in target organisms, in this case, activating expression of immune genes (Bui et al., 2023 https://doi.org/10.1371/journal.ppat.1010842).

Delivery of CRISPR machinery via inhalation or powdered form is also under investigation (Chow et al., 2021 https://doi.org/10.1016/j.addr.2020.06.001).

Thanks very much and look forward to the continued discussions on this essential topic.

Dear participants

I´m Carolina Villafañe from The Ministry of Environment of Colombia, and I am in charge of Biosafety issues and, The Cartagena Protocol.
The future applications of Sybio are wide, from environmental issues to food, health, and industrial solutions or novelties.

The Synbio is a discipline that currently has more accessibility to Young scientists than others in the history of biological sciences. An example of that is the iGEM initiative from MIT https://igem.org/

This foundation serves as an impulsor of Synbio's advance and the focus is the youth which is a critical and innovative mass of development. It is just to look for the different initiatives and start-ups this foundation has supported. I think we will see those products in 5 to 10 years in different application areas and for these reasons, a wide horizon must be considered.

Sincere regards

Hi, My name is Kemal Melih Taskin. I am a plant scientist working on plant development and biosynthetic pathways at Canakkale 18 Mart University, Turkiye. I am also a member of the scientific committee on the Genetically Modified Organisms risk assessments at the Ministry of Agriculture and Forestry.
I also agree with previous participants about near-future applications. These applications may not be realized easily before the guidelines and regulations are published. However, we require regulations that are flexible for the scientists to improve the technology and guidance for changes in public acceptance. The recent literature holds big promises such as biomaterial designs (https://www.nature.com/articles/s41563-022-01231-3), insect pest management (https://onlinelibrary.wiley.com/doi/full/10.1111/pbi.13685), synthetic cells (https://onlinelibrary.wiley.com/doi/full/10.1002/ange.202110855) and vaccine production (https://pubs.acs.org/doi/full/10.1021/acssynbio.1c00576). In Turkiye, we are preparing guidelines for genome editing technology and its applications in agriculture will be achieved very soon.

Greetings participants
As an addendum to my last post, here I provide a short table of examples of applications of that are amongst some of the most advanced. I cannot reproduce the table below without losing formatting, so I attach it as a pdf.

The examples cover the areas of agriculture, packaging and food waste, and medicine, veterinary medicine, rodenticide.

I’ve chosen the intersection of genome editing/gene silencing with synthetic biology because of the strong push in many countries to specifically de-regulate these or similar uses (as discussed in my previous post [#2630]).

This is a list of links for your convenience:
https://patents.google.com/patent/US9121022B2/en
https://patentimages.storage.
googleapis.com/b9/dc/de/c38d48ee9e7f1f/US20140215656A1.pdf
https://www.google.co.nz/patents/
EP2347759A2?cl=en
https://doi.org/10.1007/s00438-023-01998-3
https://doi.org/10.1101/2023.03.02.530790
https://doi.org/10.1016/j.tibtech.2009.09.008
https://patents.google.com/patent/US9840715B1/en
https://patents.google.com/patent/WO2014047623A1/en
https://patents.google.com/patent/ US9526784B2/en?oq=US+9%2c526%2c784+B2

With best regards
Jack

I hope that everyone had a good weekend. I would like to draw attention to convergence in the examples of near future applications being highlighted. This gives confidence both that the applications that may or may not come to potential realization in the near future can be identified with a good degree of confidence, and hence that the ‘horizon’ framing is a meaningful, robust and thus useful approach. For example, there is a lot of convergence on both ‘engineered microbes’ and ‘fuel/chemical replacements’, indicating that a focussed assessment of those two application areas (and very likely others) is justified.

The international consideration of synthetic biology needs mechanisms that can help progress deliberations beyond an ongoing situation of relative gridlock, allowing for recommendations on both acceptable and unacceptable applications to be reached in a manner that is timelier for all stakeholders.

I would like to advance the point of Prof Barro and suggest that greater support is needed for international mechanisms for capacity building in all aspects of synthetic biology.

Self-spreading vaccines for release into the environment near-future application: in process of transferring the technology to manufacturer for scale-up.

Hello…
Thanks to everyone for a stimulation discussion so far.
My name is Dr. Guy Reeves, from the Max Planck Institute for Evolutionary biology (Germany), I am an evolutionary genenetitst with interests in viral techniques intended for environmental modification. I am an inventor on a granted patent related to gene drive (EP2934093B1).

This post to a significant extent echos parts of Dr Eva Sirinathsinghji above.

In that past three years it has been reported by a commercial company that they have developed two self-spreading vaccines. One for Lassa fever virus in West African rat species and another for Ebola virus in primates.

—Time frame—
The Lassa fever virus vaccine for release into wild rat populations is reported by the CEO to potential investors (January 2023)


“ We are in the process transferring the technology to a West-African manufacturer … so that particular tech-transfer can be scaled up and then there is a possibility then obviously having somebody who can manufacture at scale to make that vaccine available in the region”.



see time point 6:10 (but see also explanatory section starting at 2:38)
https://www.youtube.com/watch?v=KHFjabspTcM

or see also
https://thevaccinegroup.com/tvg-successfully-completes-darpa-funded-transmissible-lassa-fever-vaccine-project/
https://static1.squarespace.com/static/5d927ef93f54836cb17542c1/t/5e74072e6f3a42255b9573fe/1584662333204/BIG+WIN-New+Countermeasures.pdf
https://thevaccinegroup.com/science/
note vaccine development platform that is “Evolved to spread easily through host population.”

Simply put, self-spreading vaccines are live laboratory modified viruses that are developed to spread between vertebrate hosts when released into the environment. Furthermore, that they rely on this property to (in theory) autonomously achieve population wide immunisation of wild populations and potentially also subsequent generations.
Self-spreading vaccines are always live viral vaccines that are genetically modified (i.e. LMOs). Where reported, development has occurred in biosafety level 3 or 4 facilities (Bárcena et al., 2000; Tsuda et al., 2011), though they are intended for release into the environment to spread with epidemic like properties.

Self-spreading viral techniques for use in the environment are not technically new, but until now there has been a well established norm among virologists that their use or development is highly problematic relative to existing available alternatives (Lentzos 2022).


—To date no self-spreading vaccine has been licensed (for either medical or veterinary use), despite claims otherwise by proponents of self-spreading viral approaches —.
The only ambiguous case is 2019 USA approval of the experimental release of the self-spreading Live Raccoon Poxvirus Vector (RCN-CAL/SP) in bats as an conservation measure, where it was stated that

“Because the issues raised by field testing and by issuance of a license are identical, APHIS has concluded that the EA that is generated for field testing would also be applicable to the proposed licensing action. Provided that the field test data support the conclusions of the original EA and the issuance of a FONSI, APHIS does not intend to issue a separate EA and FONSI to support the issuance of the product license, and would determine that an environmental impact statement need not be prepared. APHIS intends to issue a veterinary biological product license for this vaccine following completion of the field test provided no adverse impacts on the human environment are identified and provided the product meets all other requirements for licensing.”
https://www.regulations.gov/document/APHIS-2019-0043-0001

This statement by APHIS and the timeframe mentioned in statements by the CEO reproduced at the start of this posting raise the question of wether self-spreading viral approaches can be planing to follow the highly regulated and internationally notified testing and licensing process that vaccines follow (including the high successful oral bait vaccines for rabies which are not self-spreading).



—Relevance to CBD —
To date, proposed modified self-spreading viral approaches for use in wildlife can usefully be placed in one of two types (Lentzos 2022):
1 Experimental approaches to kill or sterilize mammalian wildlife or pests as a means to reduce their population sizes, also called wildlife management.

2 Experimental approaches to vaccinate mammalian wildlife to protect them from disease or to limit their capacity to act as reservoirs for vectored diseases.

The topic of this posting is class 2

Regulators have for decades repeatedly noted the potentially profound consequences of such viral techniques for use in biodiversity, older but thoughtful examples include (CBD 2007 or WHO 1993) . The obvious issues raised remain unresolved with no obvious current effort to address them, despite ongoing development efforts.



Given the inherent difficulty in field testing a technology that is to a significant extent designed to “get away” and the absence of any international notification for cross-border export of self-spreading vaccines or experimental releases of veterinary self-spreading vaccines. It appears the case that as the broader vaccine community focuses on moving away from higher risk approaches where effective alternatives can be developed (e.g. replacing live attenuated vaccines generated by selection), there is a considerable potential for the whole world to be surprised by a very small group of funders and mostly evolutionary biologists moving rapidly in the direction of increasing the risk profile of vaccines.

This meeting is occurring during the duration of this forum and provides some insight into the current interest in these techniques.

https://transmissiblevaccines.org/workshop-dev-vaccines/

1.
Bárcena, J., M. Morales, B. Vázquez, J. A. Boga, F. Parra, J. Lucientes, A. Pagès-Manté, J. M. Sánchez-Vizcaíno, R. Blasco, and J. M. Torres. 2000. Horizontal Transmissible Protection against Myxomatosis and Rabbit Hemorrhagic Disease by Using a Recombinant Myxoma Virus. J Virol. 74:1114–1123. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC111445/

CBD 2007. ‘Report of the Canada-Norway Expert Workshop on Risk Assessment for Emerging Applications of Living Modified Organisms UNEP/CBD/BS/COP-MOP/4/INF/13’, 39. https://www.cbd.int/kb/record/meetingDocument/58217?RecordType=meetingDocument&Event=BSRARM-01.
F. Lentzos, E. P. Rybicki, M. Engelhard, P. Paterson, W. A. Sandholtz, R. G. Reeves, Eroding norms over release of self-spreading viruses. Science. 375, 31–33 (2022). Available from: http://web.evolbio.mpg.de/HEVIMAs/


WHO 1993 Informal Consultation on Reproductive Control of Carnivores, Geneva, 16 June 1993 :. 1993. https://apps.who.int/iris/handle/10665/60995.

Tsuda, Y., P. Caposio, C. J. Parkins, S. Botto, I. Messaoudi, L. Cicin-Sain, H. Feldmann, and M. A. Jarvis. 2011. A Replicating Cytomegalovirus-Based Vaccine Encoding a Single Ebola Virus Nucleoprotein CTL Epitope Confers Protection against Ebola Virus. T. W. Geisbert, editor. PLoS Negl Trop Dis. 5:e1275.





——————-











Note that self-spreading vaccines are also described as: transmissible, contagious, horizontally-transferable, self-disseminating and founder-based vaccines. Recently a hypothetical term “transferable vaccine” has also be introduced to denote live self-spreading vaccines where transmission only occurs to individuals in direct contact with the originally inoculated individuals (Nuismer and Bull, 2020; Technology Networks, 2022). However, we are unaware of any evidence that such a class of viruses exists--particularly as viral transmissibility is always a dynamic parameter in complex environmental situations--. A precise definition of sefl-spreading vaccines can be found in box 1 of (Lentzos 20022).





Currently, there are 4 proposals for self-spreading vaccines, only one of which has resulted in recent approved releases.

1 Vaccinate African primates to inhibit their infection by the Ebola virus with the aim to limit their capacity to act as a wildlife reservoir for transmission to humans (PREEMPT, 2018; TVG, 2021; PREEMPT, 2022).
2 Vaccinate a number of rat species in West Africa to inhibit their infection by the Lassa fever virus with the aim to limit their capacity to act as a wildlife reservoir for transmission to humans (PREEMPT, 2018; PREEMPT, 2022; Regulatory News Service, 2022).
3 Vaccinate numerous North American bat species to reduce their susceptibility to an emergent fungal infection for the purposes of bat conservation. This proposal has resulted in the release of a genetically modified raccoon pox virus starting in 2019 (Rocke et al., 2019; USDA-APHIS, 2019).
4 Vaccinate various vampire bat species, that are mostly currently restricted to Central and South America, to inhibit their infection by the Rabies virus with the aim to limit their capacity to act as a wildlife reservoir for transmission to humans, but has primarily a bat conservation motivation, as highly effective human vaccines for rabies could be made available to human communities (Bakker et al., 2019; Streicker et al., 2022).


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Kerlin, K. E. 2019. $9M to Preempt Zoonotic Spillover Threats, Protect Military and Local Communities. UC Davis. Available from: https://www.ucdavis.edu/news/9m-preempt-zoonotic-spillover-threats-protect-military-and-local-communities
Lentzos, F., E. P. Rybicki, M. Engelhard, P. Paterson, W. A. Sandholtz, and R. G. Reeves. 2022. Eroding norms over release of self-spreading viruses. Science. 375:31–33. doi:10.1126/science.abj5593. Available from: https://www.science.org/doi/10.1126/science.abj5593
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Nuismer, S. L., B. M. Althouse, R. May, J. J. Bull, S. P. Stromberg, and R. Antia. 2016. Eradicating infectious disease using weakly transmissible vaccines. Proc. R. Soc. B. 283:20161903. doi:10.1098/rspb.2016.1903. Available from: http://rspb.royalsocietypublishing.org/content/283/1841/20161903
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Rocke, T. E., B. Kingstad-Bakke, M. Wüthrich, B. Stading, R. C. Abbott, M. Isidoro-Ayza, H. E. Dobson, L. dos Santos Dias, K. Galles, J. S. Lankton, E. A. Falendysz, J. M. Lorch, J. S. Fites, J. Lopera-Madrid, J. P. White, B. Klein, and J. E. Osorio. 2019. Virally-vectored vaccine candidates against white-nose syndrome induce anti-fungal immune response in little brown bats (Myotis lucifugus). Sci Rep. 9:6788. doi:10.1038/s41598-019-43210-w. Available from: https://www.nature.com/articles/s41598-019-43210-w
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Streicker, D. G., J. J. Bull, and S. L. Nuismer. 2022. Self-spreading vaccines: Base policy on evidence. Science. 375:1362–1363. doi:10.1126/science.abo0238. Available from: https://www.science.org/doi/10.1126/science.abo0238
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Questions in response to posting by Dr Eva Sirinathsinghji on 2023-03-24 17:14

Dr Eva Sirinathsinghji

I read your posting with great interest. Clearly what you are referring to as “spreadable vaccine viruses” are the same as “self-spreading vaccines” I also mention in my later post. As you clearly say this technology is clearly relevant to the objectives of the convention in that there are applications intended for use in the environment in managed and wild populations.
Question:
1 I was wondering if you had an opinion on wether the current developers of these techniques can be reasonably considered at the “early stages of research and development (R and D) ” or if there are indications that they have progressed beyond this stage?

2 Given the potential of self-spreading technologies to make transboundary movements, are you aware of any existing requirements or initiatives to register exports of transmissible live viruses or notify experimental releases targeting animals ?

3 Given the that the nations currently developing self-spreading vaccines are mostly choosing not to address the many needs within their own boarders, do you see this as an issue for the convention? It is potentially notable that earlier (subsequently abandoned) programs in the 2000s in Spain and Australia were to address domestic issues.

Thanks
Dr Guy Reeves
Max Planck Institute for Evolutionary biology (Germany)

Thank you for raising these questions on the self-spreading vaccines, which in my opinion highlight the urgent need for such horizon scanning processes as we are discussing here. It appears that some of these vaccine projects are indeed already at the trial stage, and from the information shared in your post, perhaps even at the stage of moving towards manufacturing. Given their potential for uncontrolled spread and transboundary movement, our view is that they need to feature much more prominently in biosafety discussions. As LMO viruses are involved, the provisions of the Cartagena Protocol should apply, particularly if such LMOs are intentionally exported, although there would be challenges raised by unintentional transboundary movements that may result from any field trials. Some of these are very similar to that of gene drive organisms, for which TWN has explored the regulatory landscape: See https://biosafety-info.net/wp-content/uploads/2019/10/Biosafety-briefing_-gene-drives-summary.pdf and https://biosafety-info.net/wp-content/uploads/2019/10/Biosafety-briefing_gene-drives-key-elements.pdf

The advanced nature of these projects, alongside other synbio technologies, raises several long standing critiques of global health projects that may not serve the priorities of communities that are targeted for intervention. As said in other posts for Topic 2, e.g. Lim Li Ching [#2638], Dr Wakeford [#2619], Prof Heinemann [2617] and Prof AbdelKawy [#2624], horizon-scanning processes thus need to involve meaningful participation from a diverse and broad range of actors, including potentially affected communities, indigenous peoples and local communities. Assessing multiple dimensions that encompass current state of knowledge (and gaps), including cultural, socio-economic as well as health and the environment vis-à-vis the three objectives of the Convention is crucial for such projects. Such processes need to include advancements in R&D, negative results as well as gaps in knowledge that can be used to assess projects in a timely manner, in anticipation of technologies and not instead playing catch up on those that appear to be advancing rapidly.

Thanks Eva

Dear All,
I am Renato L. Santos, a professor at the Universidade Federal de Minas Gerais (Belo Horizonte, Brazil), currently a visiting professor at the University of California at Davis, and a member of the Brazilian National Biosafety Commission.
I am enjoying and learning from everyone’s input. One potential application of SynBio that apparently has not been mentioned so far is its use to modulate the intestinal microbiota. Changes in intestinal microbiota are associated to several disease manifestations. SynBio may provide sensors for detections of disease-associated biomarkers or to induce shifts in the microbiota composition to alleviate pathologic conditions such as uncontrolled intestinal inflammation (https://doi.org/10.1016/j.cbpa.2022.102178). However, actual clinical applications may require a prolonged timeframe (10+ years) as compared to other applications previously mentioned in this panel.

Dear Participants,
Thank you all very much indeed for your very helpful contributions in response to question 1a from Topic 1 of this synthetic biology online forum.
A number of posts have very usefully highlighted specific examples of types of applications that are being worked on. However, some of these have not been supported by references to source material and/or accompanied by a potential timeframe to release (for research or commercialization). In other instances, only broad references have been made to applications of synthetic biology without any mention of specific organisms or approaches being taken. Please could contributors think about whether their submission would benefit either from references to specific organisms or approaches and/or including a reference to published information.
Also, some posts have mentioned that it is hard to predict what products or organisms will be commercialized. This is certainly true. I’d like to re-emphasize that a key aim of the forum is to gather useful information on what participants know about specific applications that are in the research pipeline and when they might potentially be ready for release. This information will be useful regardless of whether or not they will be commercialized. Then whether they are commercialized or moved further is another story, but for the purpose of this exercise I think we will benefit from having a mapping of what is coming.
In this light I’d like to highlight the document Technical CBD Series 100 on synthetic biology, which is available on the forum page as a background document, and which also has information on potential example applications and timeframes. Participants may wish to base comments on some of these examples (for example in Table 1).

Dear Professor Renato L. Santos,

I read your post with interest, I was wondering if you were aware of this  product that you could order and buy today as a consumer for 10$. 
https://zbiotics.com/products/zbiotics
While it dose not  seek to do anything as complex modulate the intestinal microbiota, it does in theory modulate it capabilities.
From the website it is clear that this is a LMO and their advertising makes this prominently and transparently clear

“B. subtilis ZB183™ – we transferred a trait for acetaldehyde breakdown from the liver into a probiotic bacteria for the purpose of helping you feel better after drinking alcohol.”
https://zbiotics.com/pages/technology

The bit that find interesting in your submission  in this context  is  “However, actual clinical applications may require a prolonged timeframe (10+ years) as compared to other applications previously mentioned in this panel.”  While the product makes no clinical claims its speed to market has been rapid.  In part because as far as I can tell there is no peer reviewed or  independent evidence that the product does what is claimed. 


“I’d love to have the budget to launch full clinical trials and demonstrate efficacy,” Oliver says. “But being required to demonstrate efficacy is too much. I’d argue that would just kill innovation for bioproducts like this.”
https://cen.acs.org/business/start-ups/worlds-first-GMO-probiotic-sale/97/web/2019/08

Do you think it possible that rather than a rigorous  scientific and  regulatory pathway for clinical applications there is also likely be alternative, much quicker routes to market and release that already exist in some countries?

Thanks

Dr Guy Reeves
Max Planck Institute for Evolutionary biology (Germany)

Dear Dr. Reeves,
thank you for bringing “B. subtilis ZB183™ into play. That is I believe a nice example for what is called a nonsense risk. The benefit (feel good after alcohol consumption) is, even if the drug stands the efficacy test, not justifiable if weighed against possible risks for human health, and there are less risky alternatives such as alka seltzer, herring, not to speak about abstinence. The example shows that we should have regulatory standards in mind when structuring horizon scanning.

Dear Dr. Guy Reeves,

Thank you for your feedback.

Here are some articles relevant to this research on using genetic intervention methods for species conservation:

A review paper I recently wrote on the topic:
Kosch TA, Waddle AW, Cooper CA, Zenger KR, Garrick DJ, Berger L, Skerratt LF. 2022. Genetic approaches for increasing fitness in endangered species. Trends Ecol Evol 37: 332-345. https://doi.org/10.1016/j.tree.2021.12.003

An article I wrote in The Conversation:
Kosch TA. 2022. Some endangered species can no longer survive in the wild. So should we alter their genes? In The Conversation.
https://theconversation.com/some-endangered-species-can-no-longer-survive-in-the-wild-so-should-we-alter-their-genes-175226

Some other helpful resources:
Redford K, Brooks T, Macfarlane N, Adams J. 2019. Genetic frontiers for conservation: An assessment of synthetic biology and biodiversity conservation: Technical assessment. Gland (CH): IUCN. 166 p. https://portals.iucn.org/library/node/48408

Novak B. 2018. Advancing a New Toolkit for Conservation: From Science to Policy. The CRISPR Journal 1: 11-15. https://pubmed.ncbi.nlm.nih.gov/31021184/

Piaggio AJ, Segelbacher G, Seddon PJ, Alphey L, Bennett EL, Carlson RH, Friedman RM, Kanavy D, Phelan R, Redford KH. 2017. Is it time for synthetic biodiversity conservation? Trends Ecol Evol 32: 97-107. https://www.cell.com/trends/ecology-evolution/fulltext/S0169-5347(16)30197-5

Phelps MP, Seeb LW, Seeb JE. 2020. Transforming ecology and conservation biology through genome editing. Conserv Biol 34: 54-65. https://conbio.onlinelibrary.wiley.com/doi/full/10.1111/cobi.13292

Powell WA, Newhouse AE, Coffey V. 2019. Developing blight-tolerant American chestnut trees. Cold Spring Harb Perspect Biol 11: a034587. https://cshperspectives-cshlp-org.eu1.proxy.openathens.net/content/11/7/a034587.long

Dear colleagues,

Many thanks for the interesting points you raised in this part of the forum.

We wanted to draw your attention to the SynBio-related activities of the European Food Safety Authority (EFSA). EFSA commissioned two horizon scans on SynBio plants and SynBio microorganisms, which were conducted by the Julius Kühn Institute (JKI, DE) and the National Institute for Public Health and the Environment (RIVM, NL), respectively, to identify SynBio products that could reach the EU market within the next decade, and which could potentially serve as relevant/hypothetical case studies to assess the adequacy and suitability of existing EFSA risk assessment guidelines for GM plants and GM microorganisms. The data gathered included “state of development” and “estimated year of commercial release”. Further details about the horizon scans are provided in the following two reports, which are available online:

1. Horizon scan of synthetic biology developments for microorganisms with application in the agri‐food sector (available at https://www.efsa.europa.eu/en/supporting/pub/en-1664)
2. Mapping of plant SynBio developments in the agri-food sector (available at https://efsa.onlinelibrary.wiley.com/doi/abs/10.2903/sp.efsa.2020.en-1687).

The hypothetical case studies used by EFSA to assess the adequacy and suitability of its existing risk assessment guidelines for GM plants and GM microorganisms are reported in the following four scientific opinions issued by EFSA:

1. Evaluation of existing guidelines for their adequacy for the microbial characterisation and environmental risk assessment of microorganisms obtained through synthetic biology (available at https://www.efsa.europa.eu/en/efsajournal/pub/6263);
2. Evaluation of existing guidelines for their adequacy for the food and feed risk assessment of microorganisms obtained through synthetic biology (available at https://www.efsa.europa.eu/en/efsajournal/pub/7479);
3. Evaluation of existing guidelines for their adequacy for the molecular characterisation and environmental risk assessment of genetically modified plants obtained through synthetic biology (available at https://www.efsa.europa.eu/en/efsajournal/pub/6301);
4. Evaluation of existing guidelines for their adequacy for the food and feed risk assessment of genetically modified plants obtained through synthetic biology (available at https://www.efsa.europa.eu/en/efsajournal/pub/7410).

We hope the information shared will be helpful.

Wishing you all the best,
Yann

Dear colleagues,
my name is Swantje Schroll and I work as a scientific consultant in the secretariat of the German Central Committee for Biological Safety (ZKBS). The ZKBS is an independent and voluntary expert panel responsible for examining and assessing safety-relevant questions of genetic engineering. The expert panel delivers position statements on this matter and gives advice to the German government and the German Federal States. The ZKBS has been monitoring synthetic biology research for more than 10 years with a focus on biosafety and the applicability of existing German and European regulations. As a scientific consultant, I have supported these activities.

The ZKBS has issued three monitoring reports so far and also carries out a continuous monitoring in form of a literature review (see https://www.zkbs-online.de/ZKBS/EN/SyntheticBiology/SyntheticBiology_node.html for more information). During this monitoring, developments matching some of the trends identified by the AHTEG have been observed. For example:
- bacteria that degrade the environmental pollutant nitrobenzene (Deng et al. 2022, doi: 10.1016/j.ecoenv.2022.114016)
- computing with bacteria that express trained neural networks (Gargantilla Becerra et al. 2022, doi: 10.1016/j.biosystems.2022.104608)
- logic gates in mammalian cells that are controlled by unnatural amino acids (Mills et al. 2012, doi: 10.1016/j.crmeth.2021.100073)

As these examples are currently in the research state, it is hard to predict when they will be released or commercialized. I guess the time-frame will not be in the near future (0-5 years).
Furthermore, the ZKBS has concluded that all research approaches monitored so far fall under the existing GMO regulations including the Cartagena Protocol on Biosafety.

Dear colleagues,

I would first like to thank Dr. Martin Cannell for moderating these discussions. My name is Sarah Agapito and I am a Research Professor in NORCE Norwegian Research Centre in Norway.

Under this question, I would like to refer to trend (b) “Increased development of technologies that genetically modify organisms directly in the field” identified by the AHTEG.

In 2020, the Brazilian Biosafety Committee (CTNBio) evaluated a product called Biomelix - guided biotics from Folium Science (https://foliumscience.com/). The product is described as a feed additive for poultry and its formula contains genetically engineered E. coli that expresses Cas9 and gRNA targeting critical genes in Salmonella (present inside the chicken gut). In the webpage, the company states that the product is in development for launch in selected territories in 2025. It is unclear what is the market status of this product in Brazil. Here it is the link to the product being listed as “approved” in the CTNBio webpage: http://ctnbio.mctic.gov.br/documents/566529/2304555/Tabela+TIMP/8c4a7218-f810-405b-94bf-a352d849f3dc?version=1.3 . In this case, the organism has been categorized outside the scope of the GMO regulations in the country.

I identify this product as genetically modified organism (GM E. coli) that modifies another organism (via plasmid conjugation with salmonella) in the field and outside the laboratory. Once the plasmid is transferred to salmonella the CRISPR system is expressed to knockout a crucial gene in salmonella, thus killing the bacteria.

In relation to trend (c) “The use of transient modification of organisms, including, for example, through the use of synthetic double-stranded RNA molecules, nano-particles and genetically modified viruses”, I would like to mention a product called EVO2106A from Evolutta Agrobiotecnologia which was approved by CNTBio in 2020. This product is described as dsRNA sprayable products to control the major pests in crops, by introducing a new mode of action that can be used alone or combine with existing technologies like pesticides (chemical and biological compounds) and transgenic plants. 

I identify this product within trend (c). However, I am not aware of the commercialization status of this product in the country.

I hope these products can bring some insight into new products and applications that are ready (if not already) in the market.

Best regards,
Sarah

Hello, my name is Taemin Woo. I have a background in Science and Technology Studies(STS) and Science and Technology Policy(STP), and currently I am working at Korea Biosafety Clearing House(KBCH) as a postdoctoral researcher. I have observed the previous online forums on synthetic biology since 2015, and I’m glad to be part of this process as a participant.

About some examples of near-future applications and their timeframe for release, I would like to emphasize that it is closely bound to the policy drive and regulatory climate of each country. The Korean government is expanding governmental investments to establish a state-led biofoundry and accelerate bio-manufacturing innovation. Along with this policy drive, there is a growing demand for industrial applications of synthetic biology in chemistry, environment, and materials. Korean large corporations are seeking business expansion through synthetic biology to overcome nation’s dependence on foreign biomaterials. Specific examples of applications are as follows: development of new biodegradable materials, acceleration of de-petroleum, production of eco-friendly products, development of biodegradable bioplastics, development of marine biodegradable plastics.

However, regulatory governance of synthetic biology is still in the early stage of discussion in Korea, so it is difficult to predict the timeframe for the release of these applications. 

Thank you.

Dear forum participants,

My name is Delphine Beeckman, and I am participating in the CBD online forum on Synthetic Biology as representative of the Belgian Biosafety Professionals (BBP, https://www.ebsaweb.eu/bbp/bbp). As a biosafety officer, focusing on the use of regulated and non-regulated biological materials in containment (e.g. labs, greenhouses, animal facilities), I am following up on trends for different types of biological materials, including synthetic biology.
With great interest I’ve been reading detailed posts with specific examples and timeframes for “near-future applications” (e.g. [#2580], [#2598], [#2623], [#2628], [#2629], [#2642], [#2654]) where it is clear that most of these are referring to a distant future (e.g. [#2628] predicting first possible field trials only 15-20 years from now, [#2654] predicting first possible clinical trials 10+ years from now) while others are indeed near future (e.g. prediction of a 5-year timeframe for engineered microbes for bio-remediation, cfr. [#2598]) or already implemented (e.g. [#2629] referring to vanillin production).
For this last example, it must be noted that although the production is involving LMO’s in an industrial contained setting and must be done in compliance with existing national and/or regional regulatory frameworks, the final end product (i.e. the actual flavor molecule) is not a living organism, and hence not an LMO.
Where LMO’s as defined by the Cartagena Protocol are involved, from within my experience in Belgium, the European continent and beyond, I can testify there is a great sense of responsibility in both the academic and industrial research scene, as well as with industrial manufacturers, to perform these activities in compliance with the applicable biotechnology/GMO/LMO regulations, with contained use permits or field trials being applied for, and implementing the preventive measures as determined by the competent authorities. Support for this statement comes from Swantje Schroll [#2672], Piet van der Meer [#2673] and Nicole Buan [#2678]. This is also in line with the observation of Ben Durham in the Topic 2, Question 2 thread that “We should recognise that the vast majority of synbio applications is of the type where the CBD and the CPB are capably 'managing', ie. the normal run of genetic modification and genome editing applications in agriculture and industrial biotech, and some in vaccine development.” ([#2600]). The latter is also being exemplified by the advent of non-pathogenic and/or attenuated vector platforms readily adaptable to include epitopes of existing and emerging diseases, and shortening the period for pandemic response to approximately 100 days (https://www.nejm.org/doi/full/10.1056/NEJMp2202669).

Looking forward to a few more final days of discussion, and with kind regards,
Delphine.

Dear Colleagues,
My name is Luke Alphey, I am a geneticist, currently employed at the University of York, with over 30 years’ experience of insect genetics. I am also a member of the UK Scientific Advisory Committee on Genetic Modification (Contained Use), which advises the UK Competent Authority on contained use of genetic modification/LMOs, including the possibility of accidental release.
Regarding potential applications, I would highlight the use of transmissible vaccines and gene drive mosquitoes, each of which have been commented on previously in the thread
Transmissible vaccines (“self-spreading vaccines”: Guy Reeves #2650 discussed these in some detail noting that several different terms are in use). These have considerable potential for vaccinating hard-to-reach wildlife populations. Developmental timescale is hard to predict; as Guy notes, developer comments seem to imply potentially within the next 5 years. I’m glad that Guy mentioned them as I feel I have seen less discussion of these than for some of the other technologies in these threads, which are important but perhaps already widely discussed. Transmissible vaccines have a wide range of potential properties; my understanding of current research programmes in this area is that they are managed very responsibly by the scientists involved, but regulation of such vaccines may be less well developed than for other technologies under consideration here.
Gene drive mosquitoes: Stephanie James [#2679] correctly notes that these have been discussed for some time, with multiple analyses leading to the positive conclusion from (e.g.) the World Health Organization and the African Union that new technologies such as genetically- and gene drive-modified mosquitoes should be investigated for their potential contribution to the continued fight against malaria and other vector-borne diseases of public health concern (citations in #2679). Despite such endorsement, deployment seems unlikely within the next 5 years, though some limited trials may occur within that timescale, perhaps of system components rather than complete systems.
Similar to Delphine Beeckman [#2683], in my experience both academic and industrial researchers in these area have a great sense of responsibility, carefully comply with extant legislation, including in relation to transportation and trans-boundary movement as well as national regulations, and consider and mitigate well in advance potential hazards. Delphine presents this more eloquently than I!
Fairly modest differences in application, for example the vector used for a transmissible vaccine, can substantially alter the risk profile. This points to careful case-by-case analysis and regulation, particularly in the early days, rather than any blanket approval for a technology (or indeed non-approval). This need for case-by-case analysis was made also by Galina Mozgova [#2660] and elsewhere.
Best regards,
Luke Alphey

Greetings Colleagues,

I am Dr. Becky Mackelprang and work as the Associate Director for Security Programs at the Engineering Biology Research Consortium, and I appreciate the opportunity to be part of this discussion. EBRC is a non-profit, public-private partnership based in the United States, but with an international presence, dedicated to bringing together an inclusive community committed to advancing engineering biology to address national and global needs.

EBRC brings synthetic biology / engineering biology researchers together to collaboratively develop research roadmaps that describe the technical advances and their applications that may be possible on short-, medium-, and long-term time horizons. Our most recent roadmap, Engineering Biology for Climate and Sustainability: A Research Roadmap for a Cleaner Future (https://roadmap.ebrc.org/engineering-biology-for-climate-sustainability/), was developed by over 90 individuals with expertise across engineering biology and other science and engineering disciplines (see Contributors; https://roadmap.ebrc.org/engineering-biology-for-climate-sustainability/contributors/). In this intervention, I will share a sample of the research and capabilities noted in Engineering Biology for Climate and Sustainability, in addition to a few other examples, divided into three themes.

Mitigation of Environmental Pollution:
Biosequestration and bioremediation are promising approaches for addressing environmental pollution, which negatively impacts biodiversity. Researchers have used bacteria and macroalgae to sequester heavy metals (see Mazur et al., 2018; https://doi.org/10.1016/j.jenvman.2018.05.086) and in the remediation of oil spills (see Adeleye et al., 2018; http://doi.org/10.4314/jasem.v22i2.1). Synthetic biology can be leveraged to engineer bacteria, algae, or other organisms to more efficiently remediate or sequester pollutants. Giachino et al., 2021 (https://doi.org/10.1093/femsec/fiaa249) describe proteins from naturally occurring bacteria that confer copper tolerance and describe how synthetic biology can be used to enhance existing “microbe-aided copper biomining” which could enable greater waste recovery. Other researchers recently used synthetic biology to design an enzyme they call FAST-PETase to degrade discarded plastics, showing that “untreated, postconsumer-PET from 51 different thermoformed products can all be almost completely degraded by FAST-PETase in 1 week” (Lu et al., 2022; https://doi.org/10.1038/s41586-022-04599-z). Dr. Owain Edwards [#2598] pointed out that synbio-based remediation or waste recycling may be reaching market readiness within a 5 year time frame.

Biosequestration of Greenhouse Gases:
Greenhouse gases and the resulting impacts of climate change are a tremendous threat to biodiversity. Some researchers are working to increase the catalytic efficiency of the major enzyme used by plants to capture carbon dioxide—RuBisCo (see Erb and Zarzycki, 2017; https://doi.org/10.1016%2Fj.copbio.2017.07.017). Plants engineered with more efficient RuBisCo are possible now at research scales, but their use at a scale significant enough to impact atmospheric carbon dioxide is not yet feasible.

Others have worked to develop novel carbon fixation pathways that could be leveraged within minimal / synthetic cells and/or in the development of artificial photosynthesis (Schwander et al., 2016; http://doi.org/10.1126/science.aah5237), though such applications are not feasible for significant carbon sequestration in the near-term.

Microorganisms can be used for point-of-source carbon capture and conversion, for example converting industrial carbon dioxide emissions into usable products. This process has recently been commercialized, and with advances in synthetic biology, could be used to generate a broad range of bio-derived products, including many currently derived from fossil fuels (see Köpke & Simpson, 2020; https://doi.org/10.1016/j.copbio.2020.02.017). Synthetic biology can play a significant role in decreasing our reliance on fossil fuel precursors and enable a shift toward renewable, biological precursors (see de Lorenz et al., 2018; https://doi.org/10.15252/embr.201745658 and refer also to Mr. Alexandre Lima Nepomuceno’s intervention [#2623]).

Conservation and Biodiversity:
The tools of synthetic biology may be used for conservation and biodiversity without directly modifying or engineering threatened or endangered species. Phelps et al., 2019 (https://doi.org/10.1111/cobi.13292) describe how CRISPR-based targeted sequencing approaches can be used to identify genetic diversity and structure within threatened populations. They also describe how ultrasensitive CRISPR-based nucleic acid detection could be used for the detection and quantification of eDNA, potentially identifying invasive species or providing important insights into the distribution of threatened species.

Synthetic biology can also be used to synthesize compounds previously “harvested” from natural sources. For example, squalene, an active component of a class of vaccine adjuvants, has traditionally been harvested from shark livers, but now is being commercially produced via fermentation (https://amyris.com/ingredient/squalene).

Finally, as noted by Dr. Tiffany Kosch [#2628], synthetic biology can be used to understand the genetic determinants of disease susceptibility and may be applied to enhance disease resistance. Dr. Kosch pointed to work on chytridiomycosis resistance in Australian frogs. I’ll also note work on the American Chestnut, which has been decimated by chestnut blight. A transgenic variety has been developed and is under regulatory review. See Forest Health and Biotechnology: Possibilities and Considerations by the National Academies of Sciences, Engineering, and Medicine in the United States (https://doi.org/10.17226/25221).

Hi Everyone,

Thank you all so much for your contributions so far, and for the moderators and hosts who made this possible.

My name is Erik Iverson, and I am a researcher at the University of Texas at Austin, in the state of Texas in the United States.

My lab studies mitochondrial function, physiology, and evolution. I was glad to see Dr. Mozgova mention genetic editing of plastids and plastomes in plants, as the editing of organellar genomes is an important frontier for synthetic biology. For mitochondrial (mt) DNA, particularly mammalian mtDNA, challenges of editing include the genetic material being inside two extra membranes, having a subcellular environment full of reactive oxygen species, and having multiple copies of mtDNA per mitochondrion and hundreds to thousands of mitochondria per cell, the majority of which need to be edited for success to be likely. Additionally, once edits are introduced into some of the population of mtDNAs, there is natural selection among haplotypes with regard to replication efficiency; this means that even edits beneficial to organismal fitness can be lost from the population of mtDNAs and/or fail to be passed on to offspring. Despite these challenges, there have been recent advances to mitochondrial editing (https://doi.org/10.1038/s41576-021-00432-x); when the limits are overcome, which might soon allow editing with the same specificity as nuclear editing, this technology will likely play an important role in facilitating adaptation and other synthetic biology applications.

One reason to target the mitochondria for editing is that, despite its limited number of genes, it has a disproportionate role in important fitness-related traits like climatic adaptation, toxin & pesticide resistance, and immunity (https://doi.org/10.1111/evo.13647, https://doi.org/10.1038/s41598-018-27805-3; https://doi.org/10.1038/ncomms4873, https://doi.org/10.1073/pnas.0802224105). Because of the difficulties in mt editing, one alternative is to replace mt haplotypes entirely with those from a closely-related species that has the desired adaptations. This is feasible through several existing techniques; the challenge is that mitochondrial genes have intimate molecular interactions with a number of nuclear genes that must be maintained for high fitness (https://doi.org/10.1002/iub.1954, https://doi.org/10.1093/jhered/esab066). Techniques that introduce too much nuclear material along with mt haplotypes will dilute the specificity of the desired modification and cause unwanted nuclear-nuclear incompatibilities, while those that introduce no matching nuclear genes will compromise mitonuclear compatibility and fitness.

Overcoming these challenges is the subject of a preprint I recently put out: https://osf.io/preprints/ecoevorxiv/gvpm9/. The preprint mostly concerns mitochondrial replacement for conservation purposes, and reports a number of specific examples in which mitochondrial replacement might help species currently threatened with extinction by warming or ocean acidification, or might even resurrect extinct mt haplotypes better adapted to warm conditions. I also discuss ethical concerns in mitochondrial replacement, such as the breakdown of reproductive isolation between species. However, the same principles would apply to mitochondrial replacement in the agricultural sphere, such as to improve crop resilience to drought stress or pathogens.

Thank you for your contributions,

Erik Iverson
erik.iverson@utexas.edu

Examples of near-future applications include
- More RNA and DNA-based circuits at lower cost with the use of machine learning for circuit design;
- More Synthetic metabolic pathway engineering for the production of naturally occurring molecules;
- Increased industrial and pharmaceutical use of organisms resulting from synthetic biology techniques;
- Increased open-air use of nucleic acids and proteins to alter traits, genes, or other kinds of genetic material; and
- Increased use of gene editing techniques to confer diseases resistance

However, there might be a need to put an obligation on Parties to submit information on applications received even before a decision is made on the use/release as a checkpoint to give an indication of which products of Synbio passed laboratory stages and are about to be used on a broader scale.

O.A.El-kawy

Submission to Topic 1, Question 1a

Dear all,

my name is Dr. Ricarda Steinbrecher, I am a biologist and molecular geneticist based in the UK, representing the Federation of German Scientists at the CBD and its meetings, and have been a member of previous AHTEGs on the issues of Synthetic Biology as well as on Risk Assessment and Risk Management of Living Modified Organisms.

Apologies for only writing now. I have however followed with interest the discussion and the detailed information provided.

I very much share the view that it is extremely difficult to predict the time frame of environmental releases of synthetic biology application, including synbio LMOs. This is the case, because such releases depend on a number of points, some of which belonging to different scientific and knowledge disciplines or to overarching levels. Such points are: a) readiness of the technology and its specific application (e.g. a specific organism (or compound or product) modified or produced through this technology; b) the ability to perform reliable risk assessments, incl. across time and space; c) the necessary regulation in place; d) international governance being in place, especially where released organisms may cross national borders; e) the agreement by indigenous peoples and local communities as well as societal agreement to the use and release of such organisms; d) the ability to ”undo” releases, i.e. the ability to stop the spread of and to recall the particular organism or genetic modification. With regard to sub-point a) readiness of the technology and its specific application, there are numerous hurdles, such as:
(i) stability of modification and organism
(ii) unpredictability of the effect of up-scaling
(ii) lab & greenhouse results often not transferable to outdoor environments (lack of replicability)
(iv) lack of knowledge and advancing knowledge: As we are constantly gaining new understanding, this can result in previously held assumptions (held as current truth) to loose validity, which again impact on the understanding of the functionality and performance of specific developments. For example, the assumption that so called silent/synomymous mutations (change in nucleic acid sequence without change of amino acid sequence) are mostly neutral in their effects has been shown to be incorrect (Shen et al. 2022). This is relevant, as it shows our lack of understanding of how the DNA and its regulation and internal interaction is indeed functioning.
Shen XK, Song SL, Li C and Zhang JZ. (2022). Synonymous mutations in representative yeast genes are mostly strongly non-neutral. Nature 606:28. doi: 10.1038/s41586-022-04823-w


In the following I want to share some of our own research with regards to horizon scanning and assessment and also provide some additional information and thoughts concerning examples of (potential) near-future applications for trends a-d identified by the previous AHTEG.

New developments have already been covered in detail in the contributions of many forum partisipants, such as by Adanna Mgbojikwe-Loto, Owain Edwards, Galina Mozgova, Jack Heinemann (thank you for that additional attachment), Eva Sirinathsinghji and Guy Reeves, most of whom have particularly emphasised the developments concerning micro-organisms, here bacteria, micro-algae and viruses, as well as showing the increasing sophistication of the technologies, techniques and tools. I will not attempt to add to this.

Information and thoughts regarding examples for trends a-d

(a) Increased field testing:

Whilst there is a high volume of research taking place using genome editing in (agricultural and other) plants, this research appears to be largely undertaken to study traits, the involvement of different genes in a trait, or to understand the role of a specific gene (or DNA sequence) in the expression of different traits. Whether or how much this will result in increased field trials is unclear, as systematic data is lacking. It is also not clear which -or which percentage- of the many published genome edited genetic modifications will eventually be carried forward into actual development. Clearer understanding and data are required.

Gene Drives Organisms:
In our group we have undertaken two separate horizon scanning surveys of current and proposed targets of gene drive development. Out of the 32 insect targets (from six different orders) identified in the scientific literature we found that “At the present time no projects are close to producing a usable and proven ‘product’. But some are closer to potential field trials, pending on regulation, risk assessment and further (technical) developments.” (Wells and Steinbrecher, July 2022 – attached). Whilst the African malaria mosquito (Anopheles gambiae) projects under A. Crisanti (Imperial College, London) are the most advanced, there have also been setbacks, including reduced genetic stability, as already reported here earlier under [#2633].

(b) Increased development of technologies for genetic modification directly in the field:

The two main technological development strands here are HEGAAs (Horizontal Environmental Genetic Alteration Agents, also known as the Insect Allies Project) and Gene Drives or Gene Drive Organisms. Both are a concern with respect to dual use, where the technology can be utilised for peaceful civilian purposes as well as for intentionally harmful and military purposes (see Reeves et al. 2018; and NASEM 2016), an aspect that has so far drawn too little attention.
Reeves, R. G., Voeneky, S., Caetano-Anollés, D., Beck, F., & Boëte, C. (2018). Agricultural research, or a new bioweapon system? Science, 362, 35–37. https://doi.org/10.1126/science.aat7664.
NASEM - National Academies of Sciences, Engineering, and Medicine (2016). Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values. Washington, DC: The National Academies Press. https://doi.org/10.17226/23405 .

Both technologies have already been covered substantially here [#2650] [#2633]. Concerning HEGAAs there is a recent publication that would be of interest in the context of technology assessment, namely Pfeifer et al. 2022, who stated: “. However, the combination of a virus-induced genetic modification of crop plants in the field using genetically modified insect vectors poses a greater risk than the hitherto existing use of genetically modified organisms. The technology's great depth of intervention allows a number of sources for hazard and a tendency towards high exposure, but it is also encumbered with notable deficits in knowledge. These issues call for a thorough technology assessment.”
Pfeifer K, Frieß JL, Giese B. Insect allies - Assessment of a viral approach to plant genome editing. Integrated Environmental Assessment and Management. 2022;18(6):1488-1499. doi:10.1002/ieam.4577
https://setac.onlinelibrary.wiley.com/doi/10.1002/ieam.4577

Our own horizon scanning surveys on current and proposed insect and non-insect targets for gene drive development find that there is a clear interest in utilising gene drives widely. We found that the vast majority of the 32 insect targets identified in the literature are single species or species complexes, however, some early stage proposals relate to broader taxonomic groups, namely the Glossina genus (Testse flies), the Scolytinae subfamily (Bark beetles) and the Thysanoptera order (Thrips).

Of the 42 current or proposed non-insect targets, the vast majority of the targets identified in the literature are single species, however some early stage proposals relate to broader taxonomic groups: the Cervid family; the Tetranychidae; snail genera hosting schistosome parasites; the Schistosoma genus, and the Myrtaceae family.

In summary we found:

(1) Proposals span a wide range of species and taxonomic groups: from mammals and fish to snails, arachnids, fungi and plants (see Table 1).

(2) In the vast majority of cases the aim is to suppress or eradicate the target.
 
(3) Compared to gene drive systems in insects, the systems in other taxonomic groups are further away from releases into the environment.

(4) A significant amount of research has focussed on developing gene drives in mice, so far with limited success, though efforts are ongoing.

(5) Development of gene drives in mice is seen by many as a pathway to applying the technology in other mammals.

(6) There appear to be significant obstacles in applying homing CRISPR gene drive technology in new species and taxonomic groups.

To see the spread of species proposed as gene drive targets, please see attached table. Our publication on this is not as yet finalised in the lay-out, but I hope to be able to post it tomorrow to this forum.


(c) Shift to environmental, conservation, agricultural and health uses:

It appears that there is a move to use genome editing and other genetic engineering or synbio technologies (including gene drives) to readily apply the trait of sterility to stop species from spreading. This would be either for invasive species that are already spreading or to prevent exotic or non-native species from becoming invasive species.
For example, to enable wide-spread use of exotic/non-native forest tree species in tree plantations for timber and pulp production, it has repeatedly been suggested, to use engineered sterility to prevent spread/escape by seed or pollen (Elorriaga et al. 2021; Briones et al. 2020; Fritsche et al. 2018).
One recently proposed trait system for sterility in trees is LEAFY, which however is also reported to have reduced growth and altered leaf traits (Klocko et al. 2021).

Briones, M. V., et al. (2020). "Efficient evaluation of a gene containment system for poplar through early flowering induction." Plant Cell Reports 39(5): 577-587
Elorriaga, E., et al. (2021). "Genetic containment in vegetatively propagated forest trees: CRISPR disruption of LEAFY function in Eucalyptus gives sterile indeterminate inflorescences and normal juvenile development." Plant Biotechnology Journal 19(9): 1743-1755.
Fritsche, S., et al. (2018). "Strategies for Engineering Reproductive Sterility in Plantation Forests." Frontiers in Plant Science 9: 8.
Klocko AL, Goddard AL, Jacobson JR, Magnuson AC and Strauss SH. (2021). RNAi Suppression of LEAFY Gives Stable Floral Sterility, and Reduced Growth Rate and Leaf Size, in Field-Grown Poplars. Plants 10(8):1594. doi: 10.3390/plants10081594

(d) Increasing sophistication of methods …

An example that might fit here is the development of anti-CRISPR technology. This is to counter, for example, the action of CRISPR/Cas based gene drives, and thus, theoretically, the spread of CRISPR/Cas based gene drive organisms. Initial work was carried out in form of transgenic mosquito lines expressing a Cas9-inhibiting protein from the Listeria monocytogenes prophage, which provided the proof of concept in laboratory settings (Taxiarchi et al. 2021).

Taxiarchi C, Beaghton A, Don NI, et al. A genetically encoded anti-CRISPR protein constrains gene drive spread and prevents population suppression. Nat Commun. 2021;12(1):3977. Published 2021 Jun 25. doi:10.1038/s41467-021-24214-5


With kind regards,
Ricarda Steinbrecher

Dear participants,

My name is Luciana Ambrozevicius, I work for the Ministry of Agriculture and Livestock. I am a former member at National Biosafety Commission in Brazil and I was a member at the SynBio AHTEGs.

There are many potential applications (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692427/pdf/fbioe-07-00175.pdf), including a number of messages in this forum highlighting very interesting specific examples. Im my opinion the horizon scanning should focus on those examples that are already in an advanced stage of development, considers current or realistically foreseeable concrete applications and the examples must be in the scope of the three objectives of the Convention.

It’s also necessary a clear distinction between the process (for example a contained use of a LMO) and the commercialized end product that is not a LMO and is subject of compliance with a different set of regulations outside the scope of Cartagena.

Thanks,
Luciana

Dear all,

I was interested in your comments about the applications of synthetic biology.

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

Synthetic biology is seen as having an impact on our society through technological development followed by commercialization. In addition to the technologies mentioned in the previous CBD Technical Series 100 Synthetic Biology, many technologies are being developed.

[0 to 5 years]
Synthetic biology is combined with microbiome research, and the construction of microorganisms for treatment is in progress. One example, E. coli Nissle 1917 strain discovered in Germany has been engineered by several companies in the US and is being developed as a disease treatment (Trends Pharmacol Sci. 2022 Sep;43(9):772-786. doi: 10.1016/j.tips.2022.02. 002.). It seems likely that these technologies will be applied to daily life in the short term.

[5~10 years]
Genome editing technology, which can be seen as one of the representative technologies of synthetic biology, is expected to be inserted to adeno-associated virus or Lanti virus and applied to gene therapy to treat rare genetic diseases or other genetic disorder (J Cell Physiol. 2021 Apr;236(4):2459-2481. doi: 10.1002/jcp.30064.).
Under the name of retrobiosynthesis, research will be conducted to design and manufacture optimal genes and circuits for the materials we want to produce (Nat Commun. 2021 Jan 8;12(1):173. doi: 10.1038/s41467-020-20423 -6.).

[10+ years]
It is expected that the construction of new functional organisms through artificial genome synthesis will take place in the not-too-distant future. Now, an artificial minimal genome based on Mycoplasma has been constructed (Cell. 2022 Jul 21;185(15):2708-2724. doi: 10.1016/j.cell.2022.06.046.). And by removing some codons, several microorganisms with extended genetic codes were created (Nature. 2019 May;569(7757):514-518. doi: 10.1038/s41586-019-1192-5.). Research on artificially producing yeast genomes is also being conducted (Science. 2017 Mar 10;355(6329):1040-1044. doi: 10.1126/science.aaf4557.). There is a lull for a while due to the high cost and the high difficulty of genome synthesis, but it is expected that there will be reports on new genome construction soon. In the case of artificial genomes, they will contribute to the expansion of the diversity of living things, but I think a lot of discussion is needed about their origins.
In addition, research on many new genomes is being conducted in the Genome Project-Write (https://engineeringbiologycenter.org/) team, and several applications will be developed here as well.

Thank you.

Hello,

My name is Mark Styczynski; I am a professor in chemical engineering at the Georgia Institute of Technology, and am also a member of the Engineering Biology Research Consortium in the USA. I have read with great interest the discussions here, and am impressed by the breadth of expertise and ideas in this forum. 

In reading about the potential near-future applications in the context of the trends identified by the AHTEG, I noticed at least one that seemed to be missing (perhaps informed by my own personal interest in the area): the development of synthetic biology-based biosensors and diagnostics, aligned with trend (c).

These sensors may be whole cells used for detection of molecules or species of interest (reviews including https://doi.org/10.1016/j.bios.2021.113359 and https://doi.org/10.3390%2Fs17071623) or they may use new technologies like "cell-free" systems that operate outside of living organisms (representative reviews including https://doi.org/10.1002/biot.202000187 and https://doi.org/10.1016/j.cobme.2019.08.005).

These technologies have significant potential to impact the environment and the human condition, as sensors can be used in a variety of contexts. They can be used for things like on-demand assessment of water contamination (https://doi.org/10.1038/s41587-020-0571-7 or https://doi.org/10.1021/acssynbio.0c00491), to help preserve environments and thus support biodiversity. There are also applications less closely tied to biodiversity, like biomedical diagnostics (https://doi.org/10.1021/acssensors.8b01163 or https://doi.org/10.1126/sciadv.aax4473), but which one could envision being applied for monitoring in support of biodiversity. One could even envision harnessing sensors meant to measure microbiota (https://doi.org/10.1038/s41467-018-05864-4) and applying it in a context to measure microscopic or macroscopic diversity in the environment (not unlike https://doi.org/10.1021/acssynbio.8b00526).  One could also envision sensors that are designed to live in situ in the environment and "report" when some phenomenon occurs, prompting intervention.

I bring these up in part because they are impactful, but also in part because they could make their way to the market in a very short time frame (less than five years). Companies including Sherlock Biosciences and Mammoth Biosciences have received large sums of investment in support of their efforts to develop sensors and diagnostics, with some technologies even receiving Emergency Use Authorizations from the Food and Drug Administration for use during the pandemic. These technologies are at our doorstep, whether in field-friendly at-home contexts or at least in clinical lab contexts.  While their immediate impacts are likely to be in the biomedical space, those impacts could easily spill over into the biodiversity space in the not-too-distant-future.  Many of the impacts of these technologies are likely to be quite positive, but as with any new technology advancements, careful consideration of other impacts (including ethical implications) will be an important component of future planning and progress.

Hello. I am Dr. Reynante L. Ordonio. I am a career scientist from the Philippine Rice Research Institute (PhilRice) working on GMO (e.g., Golden Rice, HIZR) deregulation and deployment and I also helped in crafting the Philippines’ policy on New Plant Breeding Techniques (e.g., gene editing). Currently, synthetic biology is not covered by the existing regulations in the Philippines. We have “synthetic genomics” though, which may be overlapping with synthetic biology but is more reserved and can produce GMO or non-GMO as final product.  
Among the trends mentioned in the AHTEG report, I feel that synthesis of modified viruses, cell free biology, and gene editing using codon optimized or rewritten DNA inserts (HDR) are very “near future”. In the Philippines now, we have a difficulty in accessing companies that can synthesis long and complicated sequences. Once this is overcome, synthetic biology would probably boom in the Philippines. However, the need for a separate regulation for SynBio products would be another matter for discussion as I believe Synbio does not fit perfectly in the existing GM regulation.  

Thanks for allowing me to share my views.

Dear all, this interesting discussion and the wide range of examples strongly underlines the need for comprehensive horizon scanning on Synbio. There is a lot of knowledge on individual applications and also some attempts to give broader overview. However, what is missing are comprehensive international initiatives such as operational registers with all Synbio organisms that are of relevance for the objections of the Convention and   allow to track and trace those organisms. Such initiatives will be necessary to minimize the potential negative impacts on biodiversity of individual applications as well as of interactions between Synbio organisms if released into a shared environment.

Hello, my name is Dini Zhang, working at the Nanjing Institute of Environmental Sciences (NIES) affiliated to the Ministry of Ecology and Environment of China (MEE). It is a great honor to participate in this forum. During these days, we have benefited a lot from the information submitted by expert representatives from all over the world in the field of synthetic biology. Here are some thoughts on trends in the field of synthetic biology for Theme 1.

China attaches great importance to synthetic biology research. In 2018, China launched the National Key Research and Development Program of China "Synthetic Biology", which included the main research tasks of artificial genome synthesis, artificial components and gene circuits, artificial cell anabolism, and function-specific synthetic biological systems. It focuses on solving the basic scientific problems of synthetic biological design, improving the ability to construct artificial biological systems, and innovating key technologies of synthetic biology.

At present, gene-editing technologies such as CRISPR/Cas and TALEN have been widely used in synthetic biology research. Some gene-edited crops have been commercialized, such as high GABA tomatoes using CRISPR/Cas9 technology, high oleic/low linolenic acid soybean using TALEN gene-editing technology. More gene edited crops are expected to be commercialized in the next 5 years.

Synthetic biotechnology involves many fields such as microbial cell factory, synthetic microbial consortium, artificial genomes synthesis, genome editing and gene drives. The evaluation of the positive and negative effects of synthetic biology on biodiversity conservation, sustainable use of biodiversity and beneficial sharing of genetic resources should follow the principle of case-by-case. Synthetic biology can be expected to have significant positive impacts on biodiversity conservation and sustainable use under reasonable application, but it also needs to be well tracked and evaluated. At the same time, the risk response mechanisms

Dear participants, it has been a great opportunity to read the views from participants from around the globe with different priorities and expectations, nevertheless sharing the ambition to contribute to the progress of the CBD objectives.

I am Patrick Rüdelsheim, Belgian, holding a PhD in Biology and lecturing at the University of Ghent and the University of Antwerp. My main professional activity is assisting researchers and developers in risk assessment and management of biologicals as well as compliance with biotechnology regulations. As such I have followed the Synthetic Biology developments closely and was honoured to serve as technical editor of the CBD Technical Series 100 publication.

This exchange has provided a terrific overview of developments, some still very conceptual, that highlight the broadness of the field. Grouping technology developments, the AHTEG identified 7 trends, to inform a process for horizon scanning, monitoring and assessment. As a trend refers to a general pattern or direction of change, I like to point out on the fact that different submissions to this forum are likely not illustrating a trend, are not new and/or are not in scope. For instance, null-segregants can hardly be submitted as a new element, since it has been discussed as soon as the GM plants were introduced.

Similarly, specific developments may point to new approaches. Yet specific cases should not automatically be considered a new trend. Several of the technologies may be breakthroughs and hold promises, yet will remain – as others have pointed out multiple reasons why- for considerable time in the research phase. They may also remain the exception only to be used to address very specific issues (e.g. when to use what type of gene drive system) and would not qualify as a “trend”.

Some applications are depicted as new trends, whereas they are part of evolving developments. E.g. self-spreading vaccines mark an important step for which clearly benefits/risks must be weighed. Genetically modified vaccine for veterinary use, specifically for wildlife immunization, have been released before (see e.g. https://www.biosafety.be/content/commercialisation-gmo-medicinal-products-some-figures) and self-spreading vaccines can build on this experience.

Finally, bringing developments outside of the lab is likely in many cases not a new trend. If the purpose of an application is to have products for outdoor deployment (e.g. improved crops, disease vector control, biodiversity conservation,..), reaching confined outdoor testing and eventually large scale deployment would be inherent. It marks projects reaching a level of maturity, rather than a new trend. Conversely, some applications are intended for contained use only and other shave pointed out the relevance of contained use regulations and practices as advocated by e.g. biosafety associations and the WHO.

In this respect, there is high value to provide different views on new ideas and technological developments and this forum is significantly contributing to this effort. The task ahead should result in filtering those which are truly “trends” and which should be considered as new and emerging issues that may impact, positively and/or negatively, the CBD goals.

Hello everyone.  My name is Jenna Shinen and I work in the Office of Conservation and Water, at the U.S. Department of State.  I am pleased to see the continued discussion on the forum and thank the moderators for their work and the thoughtful comments of the other participants in the forum. 

New developments in biological engineering technologies are enabling scientists to develop applications of biotechnology to address pressing challenges and opportunities.  The COVID-19 pandemic has demonstrated the vital role of biotechnology in developing and producing life-saving diagnostics, therapeutics, and vaccines that protect Americans and the world.  Although the power of these technologies is most vivid at the moment in the context of human health, biotechnology can also be used to achieve our climate and energy goals, improve food security and sustainability, secure our supply chains, and grow the economies.  These technologies are also revolutionizing biological research, advancing our understanding of living organisms, their ecosystems, and their diversity, and are becoming vital to powering the global economy.  

At the same time, application of new technologies is never without some level of risk and regulatory authorities are tasked with reviewing products to support environmental, human, plant, and animal health.  Governments, academia, and private sector partners should collaborate to review governance and oversight mechanisms to consider near-future applications in ways that reduce risk and realize the benefits of these technologies as described in Target 17 of the Kunming-Montreal Global Biodiversity Framework.  

The United States encourages independent and cooperative scientific research, development, and capacity building in many fields relevant to biotechnology and biological engineering, both domestically and with partners around the world.  Some of the research focuses on filling the gaps in fundamental understandings of biological systems, as well as technology development to speed the application of biological engineering.  We support specific programs in areas associated with stability and evolution of genetically engineered organisms, including mechanisms of containment, biosafety, and biosecurity to reduce the likelihood of adverse effects, as well as specific programs to examine the relationship between environmental pressures, ecology and evolution.  

The United States has a coordinated, risk-based system to protect the environment and human, plant, and animal health; to assess and manage any potential health and environmental risks posed by biotechnology products; and to ensure biotechnology products are safe for the environment, health, research, production, and trade.  This system facilitates oversight of near-future applications of biotechnology products that focuses on the characteristics of the biotechnology product, the environment into which it will be introduced, and the application of the product, rather than the process by which the product is developed.   

Using the current laws and regulations, the United States addresses a range of products developed using genetic engineering.  The United States re-evaluates its regulations and approaches as new information and techniques become available.  For example, the Update to the Coordinated Framework for the Regulation of Biotechnology was published in January 2017 (https://www.epa.gov/regulation-biotechnology-under-tsca-and-fifra/update-coordinated-framework-regulation-biotechnology), and the National Strategy for Modernizing the Regulatory System for Biotechnology Products, was published September 2016 (https://www.epa.gov/regulation-biotechnology-under-tsca-and-fifra/national-strategy-modernizing-regulatory-system#:~:text=This%20National%20Strategy%20for%20Modernizing,supporting%20innovation%2C%20protecting%20health%20and) 

The U.S. government welcomes the opportunity to work with partners to better understand the state of scientific advances, near-future applications of synthetic biology technologies, and to engage with stakeholders to achieve benefits and mitigate risks.

Dear All,

Following up on my earlier general observation at #2673 that  synthetic biology makes use of biological processes, which are circular by nature and which can be highly specific, below some examples of ongoing R&D at the University of Ghent, Belgium.

1. Microbial production of plant metabolites.
Plant metabolites form a chemically diverse collection of natural products with tens of thousands different molecules already identified. Different classes of plant metabolites, such as alkaloids, terpenoids and flavonoids, possess a variety of valuable attributes such as antibacterial, antiviral (including COVID-19-related coronaviruses), antioxidant and anti-cancer properties as well flavors, fragrances and colorants, among others. As an alternative to time- and resource-consuming extraction or chemical synthesis methods for plant metabolite production, microbial production offers a cheap, fast, sustainable and highly pure and specific solution. One example is the microbial production of sweeteners such as the stevia sugar RebM. In contrary to the current stevia-extracts on the market that mainly are composed from steviauside, RebA and ReD, this stevia derived sugar RebM doesn’t have a metal aftertaste, is calory-arm and is very similar to tablespoon sugar. In plant extracts RebM counts only for 0.1% of the stevia sugars’ content which makes plant extraction very inefficient and would cause a huge pressure on the stevia cultivation. Chemical synthesis is very difficult due to the chirality character of sugar molecules. Microbial production on the other hand is sustainable and very efficient. The microbial cell factory can be even enhanced by growing the microbes on waste streams instead of glucose as carbon source.
2. Microbial production of chitooligosaccharides (COS).
COS-molecules are homo- and hetero-oligosaccharides composed of β-(1,4)-linked N-acetylglucosamine (GlcNAc, A) and/or glucosamine (GlcN, D) and therefore differ in terms of the degree of polymerisation (DP), degree of acetylation (DA) and pattern of acetylation (PA), rendering them with unique characteristics for specific applications in the field of agrifood (e.g., as functional feed additives for cattle & plant biostimulants) or cosmetics and pharma. Traditionally and commercially, COS can be obtained as a complex mixture by chemical or enzymatic degradation using chitin, derived from crustaceans, insects, or fungi, as raw material. Current technologies work as complete black boxes: the final product varies from batch-to-batch, yielding COS-mixtures for which bio-activity results may fluctuate without knowing why and how to improve this. Also, this conventional route is subject to regional & seasonal fluctuations (e.g., crustacea harvest dependent) and a potential allergen threat (animal-origin). We have developed microbial cell factories (MCFs) which employ highly specific and selective enzymes such as chitin synthases (CHSs) and chitin deacety- lases (CDAs) for the production of defined COS-molecules, starting from glucose, combining superior performance in terms of product quality and quantity on the one hand, and feasibility of industrial handling on the other hand. Additionally, we can start from sustainable biomass feedstock further decreasing the environmental footprint of the production process.

3. Engineered living materials
Mycelium is the vegetative life form of filamentous fungi, which is abundantly present in natural soil ecosystems. It forms a network-like structure resulting in interesting material-like properties, for example, plastic-, foam- or leather-like, depending on the process conditions under which the organism is grown. In current applications with mycelium-based materials, the fungal organism is killed at the end of the production process. But what if we keep the organism alive during the use of the material? We could imagine that this leads to new functionalities that would completely change a consumer's perception on how to use the product. And how can we engineer such novel functionalities, even taking it beyond the biological capabilities of the fungi in their natural context? These are questions that the FUNGATERIA project consortium focuses on, by working together in an international and interdisciplinary context. To this end, synthetic biology engineering will be implemented to use a bacterial strain as a chassis for sensor-containing genetic circuits that render advanced functionalities to the ELM throughout its life cycle, either through direct activity or by influencing the growth and morphology of the fungal partner.

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

As an add on reply to 2670: At the time of the SynBio-related activity at EFSA, there was also an activity regarding Gene Drive Modified Insects, which summarized not only the different strategies on Gene Drive approaches but also other transgenic approaches in regards to biotechnological improvement of the Sterile Insect Technique (SIT).

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

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

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

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

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

I would like to draw your attention to the latest report of the working group, in which medical, agricultural and microbial-based genetic engineering technologies and their application potential are discussed. The report can be found here https://www.gentechnologiebericht.de/en/publications/fifth-gene-technology-report-2021

Dear participants,
my name is Marcelo H A Freitas, I am a virologist and my specialty is gene and protein expression control/molecular signaling. I work at the Brazilian Agricultural Research Corporation (Embrapa), member of the National Technical Commission on Biosafety (CTNBio) in Brazil and I follow discussions and negotiations related to scientific research in various international forums and initiatives (CBD, FAO, ITPGRFA, CGR,...).
Many thanks for several significant contributions. Following the Synbio theme since it originated in the CBD, and before that in the scientific field, I would like to make some remarks:
1) As mentioned in several past discussions, it is important to understand Synbio as a natural evolution of scientific research and that it presents new “tools” that allow obtaining new products and solutions more quickly and accurately. So, I agree with what was put by Mr. Jack Heinemann (2630). Some articles that may help with this consideration:
a) https://www.nature.com/articles/nrmicro3239
b) https://www.nature.com/articles/nrmicro3239
c) http://mos.org/buildingwithbiology/synbio.html

2) Synbio applications can be carried out in the most diverse fields, as already discussed and exemplified by Dr. Alexandre Nepomuceno (2623), Dr. Safendrri Ragamustari, Indonesia (2629), Mrs Carolina Villafañe (2634), Dr. Guy Reeves (2650), Renato L. Santos (2654) and Dr. Tiffany Kosch (2668). In addition, through Synbio, hitherto insurmountable challenges can be overcome, many of them related to conservation, sustainable use, management of Invasive Alien Species (IASs), among others. For more examples, please access:
a) https://www.nature.com/articles/s41467-021-21740-0
b) https://pubmed.ncbi.nlm.nih.gov/25728067/
c) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054743/

3) As many colleagues mentioned earlier, several products using Synbio have already arrived on the market and many more will arrive soon. This commercialization will depend on which type of product, but we can assume that in the next 5-10 years we will have many more Synbio products on the market.
a) https://www.nature.com/articles/s41467-020-20122-2
b) https://www.grandviewresearch.com/industry-analysis/synthetic-biology-market
c) https://www.transparencymarketresearch.com/synthetic-biology-market.html

4) As mentioned earlier, as it is an evolution of scientific research, we can benefit from what we have learned from LMOs over the last 30 years in terms of risk assessment, risk management and the entire regulatory framework. Highlighting that thanks to this intense work, we had no negative impact on human, animal, plant and environment health, much less on biological diversity. More details, please access here:
a) https://pubmed.ncbi.nlm.nih.gov/35387231/
b) https://pubmed.ncbi.nlm.nih.gov/33598046/
c) https://pubmed.ncbi.nlm.nih.gov/36122105/

5) Just as we are very careful when using these new tools, we must also be very careful when developing rules and guidelines for their use, and if this creation is necessary. This is because by creating a very restrictive system and/or based on an exaggerated interpretation of the Precautionary Approach, we can delay or even prevent scientific research and its advances.
And even if an application or product developed with Synbio is not within the scope of CBD, the creation of rules and guidelines in this forum can directly affect these new applications and products.

In response to your post Dr Sarah Agapito, it may be necessary to clarify some points so that they are not misunderstood:
a) In Brazil, CTNBio is the advisory and deliberative collegiate body on issues involving biosafety, that is, any activity or project involving alteration of LMOs;
b) In accordance with the Brazilian biosafety law 11.105/05, CTNBio is composed of an Executive Secretariat and 54 Brazilian citizens of recognized technical competence, of recognized scientific expertise and knowledge, with a doctoral degree and with outstanding professional activity in the areas of biosafety, biotechnology, biology, human and animal health or the environment. The collaboration of Ad Hoc doctors may also be requested at any time;
c) CTNBio's decisions are made in a plenary meeting;
d) According to Law 11.105/205, in its Chapter I, Art 3, Paragraph 3, there is no difference between natural and synthetic DNA and RNA molecules, therefore they are treated in the same way;
e) CTNBio's Normative Resolution No. 16 establishes the consultation and evaluation procedure at CTNBio for the collegiate to evaluate and consider whether a given product developed using NBTs is LMO/GMO or not.
If you have any doubts, or I have not been able to clarify your doubt, please contact CTNBio (http://ctnbio.mctic.gov.br/) and we will help you.

Hello, my name is Carolina Torres and I work for Island Conservation, as International Legal and Administrative Manager. I have been following the discussion on synthetic biology since 2015. Island Conservation mission is to prevent extinctions by removing invasive alien species (IAS) from islands.
The tools available at the moment to prevent the introduction, detection and management of IAS, are limited. To eradicate and control invasive species, the use of chemicals is needed (insecticides and rodenticides are the most common tool available) and this affects nontargeted species. The sustained use of these chemicals, can cause unwanted results, but it is the only method available for eradicating IAS.  
Synthetic biology is a promising and fast-growing scientific discipline. There are many researches underway on Synbio tools and applications that could help us curve the extinction biodiversity crisis and tackled one of the main drivers of extintions. Therefore, there are many  positive impacts for conservation, please refer to IUCN’s “genetic frontiers for conservation” report: https://portals.iucn.org/library/node/48408.
In terms of near-future environmental applications Genetic pest control technologies. I would expect to be field tested within 5-10 years.  You can refer to GBIRd where you can find many papers that shows the pace and progress of the research.
Here are some relevant links and papers on using genetic intervention methods for species conservation:
https://research.ncsu.edu/ges/igert/student-research/island-mice-conserving-island-biodiversity/ Progress towards engineering gene drives for population control (Raban et al., 2020)
Gene drive: progress and prospects (Wedell et al., 2019)
Combating mosquito-borne diseases using genetic control technologies (Wang et al., 2021)
Leveraging a natural murine meiotic drive to suppress invasive populations (Gierus et al. 2022)
Synthetically engineered Medea gene drive system in the worldwide crop pest Drosophila suzukii (Buchaman et al., 2018)
Gene drive strategies of pest control in agricultural systems: Challenges and opportunities (Legros et al., 2021)

Dear colleagues,

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

• Control of disease vectors: such as vectors of malaria and borreliosis.

Mainly through:

- Producing sterile female Anopheles mosquitoes and spreading this trait in the wild population using a CRISPR gene drive
- Manipulating the mosquitoes’ gender distribution. A variant of the gene drive called ‚X-Shredder‘ would ensure that predominantly male mosquitoes are born.
- Using gene drives to manipulate mice against the infectious disease Lyme disease is being considered in temperate climate zones

• Removal of invasive species from sensitive ecosystems: potentially using gene drives to eradicate invasive mice

• Control of so-called pests in agriculture: concrete plans aiming at eradicating spotted wing Drosophila (Drosophila suzukii); plant lice and Huanglongbing; New World screw-worm fly (Cochliomyia hominivorax)
The timeframe for release of these applications could be as early as 0 to 5 years.

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

Dear colleagues
Our analysis in our horizon scanning projects (see Topic 2 [#2728]) is that RNAi applications (especially RNAi Sprays) and genetically modified viruses (see the post of Guy Reeves [#2650]) are applications that are already in place or become increasingly important in the bear future.

RNAi-based GM plants are becoming increasingly important. In order to determine possible needs in risk assessment in these applications, the European Food Safety Authority (EFSA) has initiated a series of research activities since 2014, including two expert workshops (EFSA 2014, 2017), external literature studies (Paces et al. 2017; Christiaens et al. 2018; Dávalos et al. 2019) and own publications (Ramon et al. 2014; Papadopoulou et al. 2020).

Christiaens, Olivier; Dzhambazova, Teodora; Kostov, Kaloyan; Arpaia, Salvatore; Joga, Mallikarjuna Red-dy; Urru, Isabella et al. (2018): Literature review of baseline information on RNAi to support the environ-mental risk assessment of RNAi‐based GM plants. In: EFS3 15 (5). DOI: 10.2903/sp.efsa.2018.EN-1424.

Dávalos, Alberto; Henriques, Rossana; Latasa, María Jesús; Laparra, Moisés; Coca, María (2019): Litera-ture review of baseline information on non‐coding RNA (ncRNA) to support the risk assessment of ncRNA‐based genetically modified plants for food and feed. In: EFS3 16 (8). DOI: 10.2903/sp.efsa.2019.EN-1688.

EFSA (2014): International scientific workshop: Risk assessment considerations for RNAi-based GM plants. 4-5June 2014, Brussels, Belgium. In: EFS3 (EN-705), S. 1–38.

EFSA (2017): Minutes of the 118th Plenary meeting of the Scientific Panel on GMO.

Paces, Jan; Nic, Miloslav; Novotny, Tomas; Svoboda, Petr (2017): Literature review of baseline infor-mation to support the risk assessment of RNAi‐based GM plants. In: EFS3 14 (6), e391. DOI: 10.2903/sp.efsa.2017.EN-1246.

Papadopoulou, Nikoletta; Devos, Yann; Álvarez-Alfageme, Fernando; Lanzoni, Anna; Waigmann, Elisa-beth (2020): Risk Assessment Considerations for Genetically Modified RNAi Plants: EFSA’s Activities and Perspective. In: Front. Plant Sci. 11. DOI: 10.3389/fpls.2020.00445.

Ramon, Matthew; Devos, Yann; Lanzoni, Anna; Liu, Yi; Gomes, Ana; Gennaro, Andrea; Waigmann, Elisa-beth (2014): RNAi-based GM plants: food for thought for risk assessors. In: Plant biotechnology journal 12 (9), S. 1271–1273. DOI: 10.1111/pbi.12305

In addition to GM plants, RNAi Sprays have also recently been developed, in which the industrially produced RNA is sprayed onto for example plant from the outside (exogenously) as an active substance and is orally taken up by the target organism. In principle, the mechanism of exogenous RNA and RNAi-based GMOs is identical in the target organism and non target organisms.

Dear online forum participants,

My name is Felicity Keiper and I am participating in this forum as a representative of the Global Industry Coalition (GIC). The GIC has participated in previous CBD synthetic biology programs of work and Ad Hoc Technical Expert Groups. Many of our members are technology developers and have decades of experience in R&D and commercialization of biotech products, and the applicable regulatory requirements for research and commercial activities. We appreciate the opportunity to continue to contribute our experience in this work.

We welcome this question, as the focus on “near-future applications” and specific timeframes is aligned with our previous calls in this work for consideration of realistically foreseeable applications. We have also called for increased participation by those working in the field and welcome the informative contributions with specific examples and timeframes (e.g. #2598, #2628, #2690, #2708). This is the type of information that is necessary for the horizon scanning process to be useful.

In this thread, there is an exchange of views on the ability to place an application within time horizons. We agree with the view expressed in #2613 that there are clear indications that enable this as the development of an application progresses. In our view, this becomes difficult when the applications under discussion are conceptual or based on exploratory research, which we contend (as we have many times previously in this program of work under the CBD) are not a constructive use of time and resources. An additional element that can confound timelines is one that we are well experienced with – there is a difference between a biotech application being ready/near-ready for release, and the ability to do so if it is regulated (this is alluded to in #2607, #2626, #2642, #2692). This complexity applies and adds to predicted timelines for what is labelled as “synthetic biology” in this forum, as existing regulatory biotech regulatory mechanisms continue to apply (as recognized in #2672).

An example application referred to in this forum as genetic modification in the external environment is the exogenous application of RNAi-based products (“RNAi sprays”). The regulation of these products as pesticides rather than GMO cannot be generalized as “more limited” (#2630). One of the first such commercial products is currently under regulatory review as a biopesticide by the US Environment Protection Agency, and this assessment includes environmental and human health safety, and impacts on non-target organisms (see: Products | Greenlight Bioscience (greenlightbiosciences.com); with supporting literature publicly available, e.g. https://doi.org/10.1093/jee/toad034).

As a final point for this question, we note that contrary to assertions made otherwise (in this and other threads, e.g. #2617), the private sector does not operate in a vacuum but rather it collaborates broadly and participates in the usual scientific practice of publishing research and contributing to the body of scientific knowledge. Informative sources can include, for example, scientific publications, corporate communications and regulatory filings. There are several examples of developments/applications raised in this forum sourced from published patents. While these can also be informative sources, patent claims are not reliable indicators of actual “near-future” applications. 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. These reflect the possibilities for which the invention could be applied in a commercial setting, but they are not necessarily applications in development, or intended commercial activities – 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).

Regards,
Dr Felicity Keiper

dear all,

in yesterday's post I was hoping I could send around the finalised lay-out of our recent research and report of our horizon scanning survey of current and proposed non-insect targets, including vertebrates, snails, fungi and plants for gene drive development. I am please to be able to attach the preliminary publication.

wishing you all a good weekend.
with kind regards, Ricarda

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

Dear Participants,
As we draw this forum to a close, I would like to thank you for sharing examples of near-future applications of synthetic biology. We have seen many examples (and references) shared during this forum. Despite acknowledging the difficulties in predicting when a particular product might come to market or be released, it seems that for some, we have a better estimate.  Examples shared by participants of near-future applications of synthetic biology are consistent with those identified in Technical Series 100 on Synthetic Biology and include applications for biofuel and natural product replacements, engineered microorganisms, remediation products, genome-edited crops, engineered gene drives, RNA interference sprays and self-spreading vaccines, just to name a few. There have also been many technical advances, such as the increased use of artificial intelligence for the design and re-design of these applications, as well. I will work with the Secretariat to ensure that all examples and references shared are captured in the summary of these discussions.
Best regards,
Martin