Past Activities 2017-2018

Dear Participants
Greetings,
I am Taye Birhanu, a researcher at Ethiopian Biodiversity Institute, Ethiopia.
Concerning the operational definition, although synthetic biology has different interpretations among different scholars and institutions, the AHTEG (Ad Hoc Technical Expert Group) did well and compressive definition.

Horizontal gene transfer from synthetic biology organisms to native populations may lead to a change in biodiversity at the genetic level, SB organisms may have strong gene advantage for nutrient competition over native biodiversity and it may be potential invasive by unknown spreading and multiplication mechanisms.
The impact on the Access and Benefit Sharing may be digital biopiracy that when there is no template strand to follow, scientists determine the nucleotide order of the synthetic DNA by using digital sequence information.

Dear Members,
It’s a good start by Mr.Taye.
In my opinion, there should be stringent restrictions in usage of resistance genes and sterility genes as markers, both in plant and animal kingdom even at experiment conditions. Presence of these genes in the released materials obviously endangers diversity. Wide range of resistance gene markers is available and we are not sure of its known/ unknown or accidental entry in environment.
It may be prescribed to go for conventional transfer of the genes of interest by following one or two breeding cycles after T1 or T2 whatever may be the fixed stage where a stable expression of gene of interest is found. This could probably remove these markers in GMO’s. Modified organisms without these marker genes only are to be recommended for release.
Then regarding the background genetic material for modification; it should not be a poor performer. Just like in varietal release, we may concentrate to have a better performing line to be selected for final modified organism.
There should be rigorous regulations even in sequencing and synthesis of these gene fragments or their primers.
thanks

Dear participants,
My name is Barbara Livoreil, co-focal point SBSTTA in France.

I would like to report what I have read recently, hoping this may trigger discussion about how to handle these challenges in a responsible manner, starting by wondering how true they are

New or recent developments of synthetic biology would have several characteristics:
1/ they no longer only target microorganisms but expand genetic modifications to all living beings, plants, and all animal kingdom
2/ they are designed to be used "in vivo", in field experiments, no longer in confinment only
3/ although recent tools promise to deliver very precise genetic manipulations, off target effets are still prevalent and discovered and may prevent to predict with a high level of certainty the real phenotype (including behaviour) of the organism and its effects on its environment
4/ they try to overcome all the principles of natural evolution, either by inducing modifications that have so far never been observed in the wild, even possibly impossible to observe (xenobiology), or by "going faster" or "deeper" (large modifications) than evolution (and maybe not considering how the natural environment may react to this).

it seems to me that it is actually extremely difficult to predict the consequences of this, because this is very complex and multifactorial. Yet, we have long term monitoring of GMOs in the field, knowledge about invasive species, knowledge about spread of microorganisms in the wild (epidemiology)... do you think that by combining these knowledge and expertise we may be able to start developing models and scenarii of the possible advantages and negative effets of organisms, products and components from SB on biodiversity and ecosystems, including services? this could be an international endeavour, as for climate...

Ms.Barbara
I may add two things to your list.

5. Now they are edible and may become a matter of day to day concern
6. Being a part in medicine and in near future gene delivery systems they may even enter human body.

And of course we have to combine knowhow from diverse fields to arrive at a conclusion.
Hence, if we leave any loopholes unattended it may go beyond recovery.

thanks

The jargon uses off-target' to refers to imprecise targeting within the species being modified.
Non-target refers to effects on species other than the one that is the subject of the work.

Generalizations about off-target effects are premature. Their have only been a few experiments and these utilized first-generation technology that is confined appropriately to the lab. Anything proposed to go to the field will have to meet safety and efficiency criteria that address the frequency and consequences of off-target effects. Considerable efforts are being made now to engineer systems with reduced or no off-target effects.

Challenges with non-target effects are planned to be mitigated by using DNA that functions only in the target species. This too will have to be tested for safety.

Horizontal gene transfer is the primary concern of many people. Here again, design features of the technology should include the use of DNA that functions only in the targeted species.

Hello participants,
This is Syed Shams Yazdani, working at International Centre for Genetic Engineering and Biotechnology, New Delhi, and had opportunity to represent India in the last Syn Bio AHTEG at Montreal.

Thanks Mr. James for addressing important topic and clarifying concept of off-target vs non-target effect. Going by the definition given, while both are important in terms of the impact of synthetic biology intervention on the conservation of biodiversity, I believe non-target effect might be more difficult to deal with and might have larger consequences. By further advancement in the technology, it may be possible to minimize the non-targeted effect. For example, devising a system that kills the non-targeted organisms as soon as the horizontal gene transfer takes place.

Thanks prof. Yazdani and Mr.James,
As you appropriately mentioned, there are insufficient reports on these effects. In my opinion there should be stringent restrictions in biodiversity hotspots, centres of origin and centres of diversity. These regions should be protected along with active germplasm cites in a way similar to “GMO free zones” leaving the natural resources unaffected.

"it may be possible to minimize the non-targeted effect. For example, devising a system that kills the non-targeted organisms as soon as the horizontal gene transfer takes place."

Are we talking about in vivo experiments here? probably, as otherwise there would not be any non target species available. It seems to me that what you offer is a way to jeopardize the future, cause the decrease or even extinction of a non target species don't you think? all this depends on the effect of the gene transfer on the non target. But "punishing" the non-target species for something it was not intentionnally targetted may sound strange (again, I am considering biodiversity in the wild, field experiments with no or low confinment) ? especially if populations are fragmented and small... if the sequence that is transfered aims at sterilizing the organism (see some studies using CRISPR) this is obvioulsy an adverse non target effect. Some non-target effects may even never be monitored in time for remediation (especially if the population or species collapses suddenly, which maybe fine for disease-carrying mosquitos, but not for other organisms).

Rather, we would need to make sure that the modified organism CANNOT, under any circumstances, transfer genes to other species... which seems to me an impossible ambition. Let's keep in mind that the concept of species is more and more vague and that we do have more and more evidence of presence of inserts of a mixture of genetic sequences from other organisms, even in our human genomes... so we may rather choose to be more effective at predicting phenotypes from modified genotypes, and this type of research should be greatly developped to gain confidence in what we are doing (decrease uncertainty). I am aware that, at the end, it goes back to methods of selection as practiced in the "old" times?

Well said Ms. Barbera, expressive..
I wish to express my concern about “extinction” or complete elimination of a species. This applies to anything and everything inclusive of off-target, non-target and targets too.

Other than deadly pathogens, any other species should not be eliminated completely from the environment. This will cause severe damage to the ecosystem which is yet to be predicted. Just for eg. Mosquito: Instead of working on pathogens, complete elimination of mosquito may have severe damage in aquatic ecosystems and food chains as majority of its life cycle is in water bodies.

Further to state that, in case of plants this may not be possible to completely prevent gene transfers as plants outcross with the same species as well as different species of the same genus.
thanks

Dear Mr. Anthony A. James
It is nice to hear the effects on non-targets can be reduced by DNA that functions only in the target species.  Actually, the off-targets can be minimized by strengthening facilities and institutional systems required to conduct the specified synthetic biology research be it in confined or contained use.

Mr.Taye,
If we are having the products with in research facilities, the concerns about biodiversity may not arise. That may not be possible as we are getting the products in to our day to day life.
thanks

I am Dr. Motlalepula Pholo, working as a Plant Biotechnologist and also as a Biosafety focal Pesron in Botswana.

Similarly as in case of GM technology, the issue of conservation of biodiversity is of great concern.  We must bear in mind the issue of both vertical and horizontal gene transfer. What are the likelihood of prevalence of invasive species due to unintended effects of modification. For instance,  gene drive constructs targeting deletion of receptor protein, what are the impacts of other signaling pathways that might further lead to invasive species. In a nutshell, let consider the likelyhood of both potential positive and negative effect on biological biodiversity taking into the account the objective of the technology.

Dear Ms. Jeshima k Yasin,
It is easy to develop regulatory instruments for research and educational demonstration on organisms, components or products derived from synthetic biology which are mostly either confined or contained use. Furthermore, release-dependent synthetic biology applications need to be assessed by case-by case basis.

Greetings to all.  My name is Dr. Andrew Roberts and I work at the International Life Sciences Institute Research Foundation, where I have spent the last seven years working primarily on the study of environmental risk assessment for genetically engineered or genetically modified organisms.  As this is my first post, I'd like to thank the CBD Secretariat for hosting this forum and providing me with the opportunity to participate.  I'd also like to thank everyone who has contributed so far, for getting the conversation started.  I think it's worth acknowledging up front that these types of conversations can be very difficult because people enter with very different ideas of what we are talking about and why.  With that in mind, I'd like to make a few suggestions and I apologize in advance for my somewhat lengthy intervention.

First, we have been asked to discuss the potential for adverse effects from "new" developments in synthetic biology on the conservation and sustainable use of biodiversity.  I think this is laudable and necessary, but the discussion should be grounded in reality and in the context of environmental/ecological risks associated with other technologies and applications of modern biotechnology, as well as our many experiences with organisms in the environment.  We also need to keep in mind the basics of risk assessment - especially Annex III of the Cartagena Protocol on Biosafety, which seems to me to be very relevant here.  Among other things, it indicates that risk assessment is always "case by case," as echoed by Mr. Birhanu in post #8409, and intimated by Dr. Pholo in post #8408 when she mentions “taking into account the objective of the technology.”  This means we can't begin to do a risk assessment on an unspecified organism resulting from an unspecified technology and having unspecified characteristics.  Such a discussion is entirely speculative and therefore practically useless.

I would like to encourage people to be as specific as they can in making interventions.  What is the new technology you are addressing? Instead of just speculating that it might damage the conservation and sustainable use of biodiversity, explain what it is that you see as potentially damaging, and how that damage might occur.  Is your view hypothetical or based on some evidence?  In this way, we might have an informed discussion rather than just producing a list of speculative harms.  For example, while it may be conceivable that “synthetic biology might harm biodiversity through gene flow,” it’s not particularly useful point of departure.  I think it’s worth keeping in mind that gene flow – whether vertical or horizontal – represents a pathway of exposure.  Whether that exposure leads to harm or damage to the conservation and sustainable use of biodiversity is dependent on many things – including the nature of the gene, its function in the exposed organisms, what the organisms are that are exposed etc.  But simply having a new gene or genetic element present in a population is not, by itself, obviously or necessarily harmful to biodiversity. 

Finally, I think it’s worth pointing out that the utility of these kinds of discussions is not from re-inventing knowledge from other fields.  At present, we have ample experience in laboratory research with microorganisms, including pests and pathogens, plants and animals, known invasive and damaging species as well as disease vectoring insects.  All of these organisms pose risks to the conservation and sustainable use of biodiversity, and are managed accordingly.  In the context of these activities, it’s difficult to understand what we would expect the inherent risks to be associated with “synthetic biology” broadly that would be different than the risks associated with these other organisms.  An enhanced green fluorescent protein is arguably synthetic biology, but I’m hard pressed to imagine any potential adverse effects on biodiversity resulting from this protein and even more challenged to identify any risks that would not be equally relevant to a “natural” green fluorescent protein.  

None of this should be construed as criticism of the goals or intention of the forum.  But I think if the discussion is going to provide value to future considerations of risk assessment for synthetic biology applications, we should try to avoid sweeping generalizations and unsupported statements and instead be specific in our consideration of potential adverse impacts.

POSTED ON BEHALF OF PETER KWAPONG
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Dear Jeshima
Thank for your contribution. It is very true gaps in ecosystem will be created if species are eliminated completely.
Thanks. Peter

POSTED ON BEHALF OF PETER KWAPONG
------------------------------------------------
Thank you Barbara for those beautiful contributions
Peter

For my understanding, this topic 1 requires to answer the question of what are the potential impacts (positives and/or negatives) of synthetic biology on biodiversity?
Synthetic biology may propose solutions to some of the greatest challenges facing the environment, such as climate change and scarcity of clean water, but also poses a high risk for natural ecosystems. The introduction of novel, synthetic organisms may therefore have both constructive and destructive effects on the conservation and sustainable use of biodiversity. There exist some benefits and risks of using synthetic biology.
As benefits, several synthetic biology applications aim to respond to environmental challenges, including those associated with energy, wildlife and agriculture. These may have indirect or direct positive impacts on biodiversity. For example, some GM crops have provided both livelihood and conservation benefits. For instance, Bacillus thuringiensis (Bt) cotton, genetically modified to produce an insecticide, has been shown to reduce pest damage in developing countries such as Cameroon and India, contributing to agricultural growth in small-scale farms. This is in line with the the Aichi Biodiversity Targets 11-13 (Improve the status of biodiversity by safeguarding ecosystems, species and genetic diversity). It is notice that in this way, synthetic biology could reduce the impact of human land use on biodiversity, by, for example, reducing the need for pesticide use (which can have negative impacts on non-target wildlife). Unfortunately, In Cameroon, as compare to India, this new technology is not yet used by small-scale farmers, only the Government. Farmers are very reluctant.
Furthermore, habitats currently unavailable to wildlife due to energy installations for example could be made available by the introduction of new methods of energy production, such as algae that use carbon to produce fuel.
Synthetic biology can be used to synthesize products currently extracted from plants and animals. Engineering biosynthetic pathways provides an alternative and cost-effective method of producing drugs of natural origin, such as morphine and aspirin. This may reduce the pressure on species that are currently threatened by hunting or harvesting (CBD, 2015a).
More immediate benefits could be derived from protecting at-risk species by genetically modifying bees to be resistant to pesticides or mites for example. It is also possible to use synthetic biology for control of disease vectors. Using gene drive systems, it is possible to change the genomes of populations of mosquitoes to make them less dangerous (e.g. resistant to the parasite that causes malaria). Gene drive systems can also be used to lessen the threat from other insect vectors of diseases, reverse pesticide resistance or eradicate invasive species, which are significant threats to biodiversity.
In addition to these benefits, there are non-discriminatory risks. Indeed, the escape or release of novel organisms into the environment could radically and detrimentally change ecosystems. Genetically engineered microbes could have adverse effects in the environment due to their potential to persist and transfer their genetic material to other microorganisms. The organisms may become invasive, and, by exchanging genetic material, form hybrids that out-compete wild species. Indeed, the transfer of genetic material to wild populations is a major risk. Genes could be transferred through horizontal or vertical gene transfer, which could lead to a loss of genetic diversity and the spread of harmful characteristics. Even without genetic transfer, these organisms could have toxic effects on other organisms such as soil microbes, insects, plants and animals. They may also become invasive and have an adverse effect on native species by destroying habitat or disrupting the food web for example.
For example, gene drive systems designed to suppress populations of disease vectors could have unintended consequences for biodiversity, such as introducing new diseases by replacing the population of the original disease vector with another. Using gene drives to change entire populations very rapidly could have other unforeseeable implications, including potentially devastating effects on entire ecosystems.
Similarly, while replacing natural products with synthetic ones could reduce pressure on natural habitats, it could also disrupt conservation projects and displace small-scale farmers (CBD, 2015a).
Reference:
Convention on Biological Diversity (2015a) Synthetic biology. Montreal, Technical Series No. 82: 1-118.

Several posts have mentioned horizontal gene transfer as a potential risk.

Horizontal gene transfer events (HGT: acquisition of genetic material other than from a direct ancestor, acquisition from an ancestor being “vertical transmission”) is frequent in some microbes but very rare in higher animals (metazoans) and plants.  For example, Loreto et al (Heredity 2008 100:545-554) discuss the evidence for putative HGT events involving transposable elements (TEs) in Drosophila species.  Transposable elements have built-in mechanisms facilitating HGT, yet even between these large-population-size, relatively short-generation species only 101 putative events involving 21 multi-copy elements were detected over tens of millions of years.  Numerous other studies have drawn similar conclusions. HGT events between microbes and metazoans, e.g. from Wolbachia to their insect hosts are also known, again facilitated by specific features of this biological system, but also rare.

Following a classical definition of risk as likelihood x hazard, likelihood of HGT for synthetic/engineered genetic elements in metazoan systems is clearly extremely low on realistic timescales (decades or centuries).

It is harder to draw general conclusions about hazard as this is much more case-specific.  A key consideration may be whether the introduced element is likely to spread within the new recipient species following such (extremely rare) HGT event.  This will likely require the element to be functional in the new species and have a means of spreading, e.g. confers a fitness advantage or has selfish DNA properties.  Spread simply by stochastic means (genetic drift) from an initial introduction is highly unlikely for a neutral element; in practice engineered elements are likely to impose at least a small fitness penalty, making stochastic spread correspondingly less likely.  Likelihood of spread given an HGT event can be assessed in advance, as part of the development or regulatory process, and in many cases can be mitigated by design.  Tony James [#8398] addresses one aspect of this by suggesting that “Challenges with non-target effects are planned to be mitigated by using DNA that functions only in the target species” [#8398&#8399] , and another possible approach “For example, devising a system that kills the non-targeted organisms as soon as the horizontal gene transfer takes place.” [#8400].  Barbara Livoreil [#8403] framed this second approach as “”punishing” the non-target species…”, however with observed HGT rates it is highly unlikely that even a single individual would be affected, let alone a species; this is a precautionary approach to address the potential hazard (in cases where one is assessed to potentially exist) - the likelihood remains extremely low.

Note that the above analysis relates strictly to HGT; movement to non-target populations by hybridisation (vertical transfer) is a different issue.  That might include transfer to non-target populations of the target species, or to other species capable of forming fertile hybrids with the engineered organism.  For animals, fertile hybrids can only be formed between extremely closely related species, if at all, but may be more of an issue in plant systems.

I concur with the views articulated by Mr. Andrew Roberts.  One can only consider risk assessment of a well defined entity, and this must be done on a case-by-case basis.
Best regards to all,
Ethan Bier

Thanks Mr.Andrew for thought provoking detailed analyses.

I will try to answer few questions raised #8408 – the network analyses of genes and system biology approach will be giving the impact of overexpressing or altering a gene in overall as well as signaling effects too. (not a speculation. We are working on this aspect).

By generating a new genotype and phenotype in fact we are enriching the diversity as an immediate effect. But if this genotype dominates and suppress others then it will be like destroying the dinosaurs to grow mice.

#8409 –I too insist the same opinion. Release of any modified organism should be analysed case by case and as I already mentioned in #8385 “there should be stringent restrictions in usage of resistance genes and sterility genes as markers, both in plant and animal kingdom even at experiment conditions. Presence of these genes in the released materials obviously endangers diversity. Wide range of resistance gene markers is available and we are not sure of its known/ unknown or accidental entry in environment”. 

#8410 – I think nothing discussed here so far is speculative. If speculative, then theories and hypothesis holds fit at many cases. So it may serve the purpose in many instances. Apart from that I hope every member has given examples and case by case details only. Only thing is events are not mentioned. If that is also needed then we may do.

#8410 (“while it may be conceivable that “synthetic biology might harm biodiversity through gene flow,” it’s not particularly useful point of departure”)- not only in synthetic biology, conventional open pollination also harm biodiversity. Again for eg. I’m growing a rice variety next to GMO rice. The chances of contamination through pollination are very less because it is a self pollinated crop. I can maintain my non-GMO line as pure as possible unless there is any physical admixture. Diversity in this case be maintained unless there is any mutation or selection by natural forces.
If we are growing a set of cross pollinated crop like maize germplasm next to GMO, we will get all effects, harvested product may be a synthetic or a composite and starting from zinnia effect; everything will be present. Hence, we are losing diversity.  This occurs in nature as there are wild relatives, native lines, cultivars and farmers varieties etc.. in the ecosystem nearby any planted GMO. Leave them with any GFP fusions. After few generations everything will be glowing.

#8410 (“An enhanced green fluorescent protein is arguably synthetic biology, but I’m hard pressed to imagine any potential adverse effects on biodiversity resulting from this protein and even more challenged to identify any risks that would not be equally relevant to a “natural” green fluorescent protein” )– a GFP present in a modified organism is not posing any threat to biodiversity as it remains as such in experimental setup or confinement. In this case as you said we can only speculate the impact as we can’t let this go and contaminate everything to study the impact. So for example, if a fusion protein is released (means a GMO with fusion protein containing GFP) and is outcrossing (means it is open pollinated crop) with other members of the species. This introduced gene is overexpressing and dominates to produce its own genotype. Hence it expresses epistatic effect over other alleles and leads to genetic drift of the remaining alleles and is eliminated from the population. After few years we may be having only this allele in that crop species. But let us have one more assumption that this protein is a susceptibility protein to a major disease. There is an endemic / epidemic spread of that disease. We will lose the species completely. Now please tell me whether this a threat to biodiversity or not ? Then obviously we should know each event case by case. If we need best example for this, we do have potato famine. Only thing missing in this example - GFP is not present and it is not a product of synthetic biology. But in my opinion synthetic biology takes its candidates from existing environment. Hence including GFP, examples can serve the purpose to explain the impacts on large scale and in many instances hypotheses and speculations will help.  

thanks

Most welcome and thank you Mr.Peter and Ms.Dina

Dear participants,

My name is Ruth Müller. I head the Genetics and Ecology Platform of PoloGGB in Italy. I work on the ecological risk assessment of genetically modified mosquitoes under contained conditions.

I would like to clarify that no one is proposing to eradicate vector mosquitoes. The common goal of colleagues working on genetically modified mosquitoes (as far as I am aware) is to reduce the population size of mosquito vectors or to make mosquitoes immune to the pathogen. The reduction of mosquito populations is also the goal of present vector control programs mainly based on preventive measures and chemical insecticides.
Just to mention, insecticides can have major impacts on biodiversity. Hence the development/application of synthetic biology for control of disease vectors may provide a great benefit for protecting biodiversity by minimizing chemical release to the environment. Though I completely agree; we need to assess the ecological effects of GM mosquitoes carefully under contained, but near-natural conditions as best we can before releasing GM mosquitoes into the field.

Thanks Ms. Makueti Josephine,
I wish to share my opinion

#8414-(reducing the need for pesticide use (which can have negative impacts on non-target wildlife)- In fact, Indian farmers are using more chemicals than recommended and we couldn’t see any reduction in usage of chemicals.

(This may reduce the pressure on species that are currently threatened by hunting or harvesting)- on the other way it will reduce farms to labs and there may not a situation to cultivate the native plant. Please keep watching synthetic vanilla flavor. It might have taken the rights too. We may discuss while going for ABS regarding this issue again.

(More immediate benefits could be derived from protecting at-risk species by genetically modifying bees to be resistant to pesticides or mites for example)- it may be good if the honey is not contaminated. But it will contaminate not just honey the bees population and colonies too.

Biodiversity protects everything as a whole; as an ecosystem. If something is harmful to human, that doesn’t mean that we have to eliminate them, because, we actually don’t know their indirect benefits. Caterpillar eats leaves but they are the beautiful butterflies after few days, flying from flowers to flowers making entomophily effective.

I think I’m against to vector control. Control the pathogen or modify the host is my opinion which I expressed earlier also.

We have to register one thing strongly. Synthetic biology is again a tool just like any other breeding technique. A breeding technique should develop a new variety adding to biodiversity. It should not be deleterious to anything available in nature. No eradication except deadly pathogens.

thanks

Many mosquitoes associated with the transmission of human diseases breed in temporary water habits (small containers of human origin [trash]) with no established positive ecological significance. Indeed many of these sites are in recognized violations of ecosystems, tire and trash dumps. Regional elimination of the mosquitoes in these would not represent a threat to any pristine ecology.

read 'habitats' not 'habits'.

dear Ms. Ruth,
We accept the fact that they are trying to reduce the population. But a sterility gene will eliminate the species. Let them modify the mosquito into a water spider like organism, let us modify them with chewing mouthparts instead of piercing and sucking mouthparts, let us modify the hind wings so that they may not fly far away. But a sterility gene in an organism will bring them to the museum either it may be a plant or a fly.
thanks

Dear James,
If a regional elimination is possible and not going to spread that may be good. But we are thinking of possible gene transfers across the populations and their impacts. The most important point is in true ecosystem, populations are not strictly isolated or confined.
thanks

Dear participants
My name is Delphine Thizy, I work for Imperial College on a non-for profit consortium called Target Malaria developing new technologies to fight malaria transmission.

I agree with posts #8410 from A. Roberts and #8417 from E. Bier about the need to be specific in the risk assessment and to consider specific applications rather than then looking at the modification tool itself. This is aligned with the recommendations from the National Academy of Sciences Engineering and Medicine in its report Gene drives on the horizon, Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values.

I agree with post #8408 from M.Pholo calling for a risk/benefit analysis for such technologies. This is aligned with the recommendations from the European Academies Science Advisory Council in its report Genome editing: scientific opportunities, public interests and policy options in the European Union (chapter 3 on gene drive technologies).

I would therefore disagree with post #8422 from J.Yasin against vector control. The exemple of malaria shows the importance of vector control. Malaria is a deadly disease. In 2015, 212 million cases were reported and 429,000 people died, 92% of which were on the African continent (WHO World Malaria Report 2016). Beyond public health, malaria is also a burden on African economy and development with an estimated cost of 12 billion USD per year. Available WHO recommended methods have achieved important reduction in both malaria incidence and mortality. According to WHO (fact she malaria works report 2015), 79% of cases averted have been so thanks to vector control (mainly bed nets and indoor residual spraying). This means 663 million cases averted between 2001 and 2015.

However there are two important challenges going ahead: first one is the difficulty to achieve complete malaria eradication. According to WHO global technical strategy, even with an important increase of funding – up to 9 billion dollars in 2030 while only 2,9 billion are currently available – 65 countries would still have malaria in 2030. The second challenge is the increased risk of resistance, both insecticide resistance and drug resistance. Therefore there is a consensus amongst the malaria community that new tools are needed to achieve malaria eradication.

The use of gene drive to either reduce the number of malaria vectors or to affect the ability of mosquitoes to transmit the disease is considered as one of the potential complementary tools to achieve malaria elimination. It does require responsible science and case-by-case risk assessment to ensure that the technology development takes into account stakeholders' concerns and that appropriate studies are carried-out in this direction.

Some concerns raised here, have been considered in a recent publication "Results from the Workshop “Problem Formulation for the Use of Gene Drive in Mosquitoes” that I attach for reference.

Accompanying those who have “moved on” from the thread [#8367] to contemplate conservation and synthetic biology, I find that the flaws of the AHTEG definition resurface. At what taxon is synthetic biology relevant to conservation? At what taxon should the Parties conserve?

The CBD is clear on the second question which may shed light on the first. Biological diversity “includes diversity within species” (Article 2), i.e. everything. Much useful natural information is unique to individuals within a population and even to an individual at a moment in time. The former is well documented in the case of Moore v. Regents of the University of California (1990); the latter, in the poison-dart frog (Angerer 2015). The concept that usefulness for R&D may lie at the level of the individual is also not new. Artificial selection has proceeded in animals and plants for millennia through exploitation of variance within a population. With the meteoric rise of the “-omics” disciplines and the collapse of associated costs, we now have repositories of natural information of individuals and even phenotypical expressions.

Release of synthetic biological products may displace natural information through competitive exclusion by the released product. Synthetic biology, therefore, is relevant to conservation at the level of individuals and ephemeral phenotypical expressions.  It would be absurd to sequence all individuals and cyro-preserve all expressions over their lifetimes. Nevertheless, sequencing of select individuals and cryopreservation of certain phenotypical expressions is practical and occurs.

How should Parties manage the risks posed by synthetic biology to unknown diversity within populations, which also has unknown future use? Inasmuch as erosion will occur before Parties gain the relevant knowledge, incentives are better than penalties. Should the Parties shift the definition of the object of access from “genetic materials” to “natural information” and apply the appropriate economics, incentives will emerge to preserve the natural information found at the level of the individual or temporal expression.

In an attempt to “move on” from the highly flawed AHTEG definition, we will find ourselves drawn back to examine its usefulness and operability.  Economists would suggest that the “lengthy negotiations” of the AHTEG be regarded as a “sunk cost” (Samuelson and Nordhaus, 2005, 164).


Angerer, Klaus. 2015. Case Study 1: Epipedobates anthonyi under ‘bounded openness’. Appendix I to Genetic Resources as Natural Information: Policy Implications for the Convention on Biological Diversity by Manuel Ruiz Muller, 98-109. London: Routledge.

Samuelson, Paul A. and William D. Nordhaus. 2005. ECONOMICS, 17 edn. New York: McGraw-Hill Irwin.

A few brief comments on GM mosquitoes, since the case has been raised specifically (or rather, set of cases, since there are numerous products/approaches under development that may differ significantly in potential risks and benefits).

No one is proposing to control by genetic means all mosquitoes in an area, let alone globally [Ms Muller notes another aspect of this in #8421].  All proposed methods based on GM mosquitoes of which I am aware - and I have been working in this field for more than 15 years - depend strictly on vertical transmission for their action (i.e. work exclusively through formation of successful mating between the modified mosquitoes and wild type mosquitoes).  Since mosquito species, as with other animals, cannot form fertile hybrids except with their own species (or, in some cases, extremely closely related species within a species complex), this restricts the direct effect of the modification to the target species.  There are several thousand named species of mosquito; no such intervention will come anywhere near to directly affecting “all mosquitoes”, even in an area let alone globally.  Rather, such interventions target specific major vector species transmitting major human pathogens, principally Anopheles gambiae and Anopheles stephensi (malaria) and Aedes aegypti (dengue, Zika and other viruses).  Regarding assumptions of broad ecological harm from controlling these species by genetic methods, these species are not known to be keystone species in their ecological contexts and indeed have been subject to various types of non-genetic control for many years.  In the case of Aedes aegypti one might further note that the populations being discussed for control at present are relatively recently introduced invasive populations; suppressing or eliminating them might be considered bioremediation rather than harm, although the principal underlying motivation would likely be disease control rather than environmental restoration.

Current methods of vector control, e.g. use of chemical or biological toxicants, are far less species-specific and so arguably likely to have broader environmental impact, at least in terms of which species are directly affected by the intervention.

Ms Muller also commented “I completely agree; we need to assess the ecological effects of GM mosquitoes carefully under contained, but near-natural conditions as best we can before releasing GM mosquitoes into the field” [#8421] - this is sensible advice for future programmes, but I also note that there have been field releases of GM mosquitoes in several countries since 2009, with no reported negative impacts on human health or the environment [those mosquitoes did arguably contain a “sterility gene”, yet did not, contrary to #8425, eliminate the species, nor was that a remotely feasible outcome].  That positive precedent does not obviate the need to consider future releases on a case-by-case basis, but it does provide some evidence, and indicates that an automatic presumption of negative impact would be inappropriate.

Target Malaria offers an interesting example of how 'contained use' issues are not so easy or clean cut when it comes to synthetic biology and, in particular, synthetic biology applied to pathogens or novel pathogen-like organisms, of which a gene drive mosquito with intended deleterious effects on a wild species are a prime example.

Research and development of such synthetic biology organisms incorporating gene drives or similarly-intended technologies - that is, which are intentionally designed to harm or even eradicate wild populations - is fraught with serious biosafety concerns. It would be extremely difficult to argue that such R&D should not take place at P3 (BSL-3) or higher containment, given that the risks of inadvertent or unauthorized release include, at a minimum, eradication of vector species (which has other ecosystem roles).

These concerns and risks are heightened in the case of many developing countries (and their neighbors) where appropriate facilities and experience safely operating them - including the additional challenge of flying insects - may not be strongly present.

Indeed, in this respect, it is necessary to question the wisdom of Target Malaria's plans, as articulated by its representatives in Cancun. (Please note that Target Malaria has represented its plan differently in different occasions.)

More generally, this example should lead us to more broadly consider the novel implications of synthetic biology for contained use.

Edward Hammond

I appreciate the observations registered by Mr.Edward.

thanks

Mr. vogel,
Kindly frame a revised definition from your side. In my opinion, I think you may start that side track. Obviously members will add their opinion to that. Efforts will never go waste. We may see how many positive comments are arising to that. Having an additional definition unaccepted is not a problem.
You may redefine this earlier posted one or a fresh one please.
I’m placing the copy posted in #8371 (We may propose to modify the definition akin to “synthetic biology is an applied modern life science that combines genetic resources and technology to facilitate and accelerate the understanding, design, redesign, manufacture and/or modification of genetic materials, living organisms and biological systems for the direct benefit of the mankind without altering or by enriching the biodiversity”.)
thanks

Dear Ms. Jeshima K. Yasin,

Thank you for engaging the issues raised in [#8367], [#8393] and [#8428] in your request for an alternative definition of synthetic biology [#8433].  The failure of the AHTEG definition to satisfy the Rules of logic in crafting definitions can be contrasted with the definition suggested by The Peruvian Society for Environmental Law (known by its acronym in Spanish, SPDA):

Synthetic Biology: the extremely intensive use of artificial information in the manipulation of natural information (Peruvian Society for Environmental Law 2016, p3).

The succinctness of the SPDA definition requires unpacking:

“Extremely” refers to a very high degree and can be quantified as a percentage of the normal distribution, say, the upper 5%;
“Intensive” refers to a high concentration in the use of a factor vis-a-vis other factors (e.g., capital or labor-intensive);
“Artificial” refers to something produced by man. Implicit is the notion that the product is intentionally man-made (e.g., antibiotic resistance would, therefore, not be artificial but natural);
“Information” can be interpreted as the second meaning found in Webster-Merriam: “the attribute inherent in and communicated by one of two or more alternative sequences or arrangements of something (such as nucleotides in DNA or binary digits in a computer program) that produce specific effects”; 
“Manipulation” means something managed or utilized skillfully;
“Natural” means in accordance with inherent characteristics.

The SPDA definition allows evaluation of diverse biotechnologies by the intensity of artificial information in the manipulation of natural information. A classification of an endeavor as “synthetic biology” can facilitate both ABS and measures for biosafety. Inasmuch as biosafety will be taken up in Topics 3 and 5 of this Online Discussion, I will address ABS which relates to the three objectives of the CBD, mentioned in [#8367], [#8393] and [#8428].

At the side events of COPXIII, many scientists deployed the metaphor of LEGOs to explain synthetic biology to the non-scientists present. I shall do likewise. If the pieces of LEGOs are amino acids then the most extreme manipulation of natural information---pure synthetic biology---would be a living organism built solely through knowledge of the chemistry and physics of the amino acids assembled. Most endeavors labeled as “synthetic biology” are far from this absolute. They intensively use a variety of techniques to manipulate natural information, disembodied and transmitted digitally. Although not pure synthetic biology, the endeavors may be so extreme in the intensity of use of artificial information as to qualify as synthetic biology by the SPDA definition.

To what extent will there be an ABS obligation? If the metaphorical LEGO pieces have already appeared in expired patents, then those pieces, like the patent, are also in the public domain. This will be the case for pure synthetic biology. The intellectual-property-protected synthetic biotechnology will have no ABS obligation whatsoever. In such scenarios, none of the LEGOs are at risk of loss. However, if the natural information does not appear in an expired patent, then an ABS obligation would arise.

Users who hail from synthetic biology should not blanche. The economics of information supports the notion of “bounded openness” whereby natural information flows unencumbered, thereby facilitating access and R&D (Vogel, et al 2011). Use of natural information is disclosed in the application for intellectual property protection and only commercially successful products pay royalties.  The benefits will be be distributed according to the geographic share of habitat in the countries of origin, which is fair, equitable and efficient (Vogel et al 2018).



Vogel, Joseph Henry, Klaus Angerer, Manuel Ruiz Muller and Omar Oduardo-Sierra (2018, forthcoming) “Bounded Openness as the Global Multilateral Benefit-Sharing Mechanism for the Nagoya Protocol” in Charles R. McManis and Burton Ong (eds) Routledge Handbook on Biodiversity and the Law. London: Routledge.

Vogel, Joseph Henry, et al. (2011). The economics of information, studiously ignored in the Nagoya Protocol on Access and Benefit Sharing. Law, Environment and Development Journal 7(1):51-65.  English: http://www.lead-journal.org/content/11052.pdf ; Arabic: http://www.lead-journal.org/content/11052d.pdf ;  Chinese: http://www.lead-journal.org/content/11052e.pdf ; French: http://www.lead-journal.org/content/11052b.pdf ;  Portuguese: : http://www.lead-journal.org/content/11052c.pdf ; Spanish: http://www.lead-journal.org/content/11052a.pdf

Peruvian Society for Environmental Law (SPDA) (2016) ‘Submitted view for the Updated report and synthesis of views in response to paragraph 7(b) of Decision XII/24; and Report of the Meeting of the Ad Hoc Technical Expert Group on Synthetic Biology’, http://bch.cbd.int/synbio/peer-review

Dear colleagues,

I am Robert Friedman, a researcher with the J. Craig Venter Institute, which is a non-profit, genomics research institute in the United States with an active synthetic biology research program.  I was a member of the first Synthetic Biology AHTEG that met in Montreal in September 2015.  Given that experience, I very much appreciate the open and diverse discussions of the online forum so far.

Our charge, from both the Conference of the Parties and our moderator Casper Linnestad, is to focus on the “recent technological developments within the field of synthetic biology”.  Several participants have noted the importance of focusing on specific examples, that is, following a “case-by-case” approach.

Several participants have already identified one of these recent developments, that is, current research to engineer mosquitos to help control malaria.  Though scientists had been working for many years to develop “gene drives” for this purpose, in November and December 2015, two independent groups of scientists made significant progress by using new CRISPR gene editing approach.  Delphine Thizy [#8427] mentioned the recent review by the US National Academies of Sciences, Engineering, and Medicine, “Gene Drives on the Horizon”.  The World Health Organization (WHO) Vector Control Advisory Group (VCAG) is also reviewing these applications and concluded “While recognizing the many challenges that lie ahead, VCAG encourages further development of tools utilizing gene-drive based technologies. (Available at: http://www.who.int/neglected_diseases/vector_ecology/resources/WHO_HTM_NTD_VEM_2017.02/en/ ) Both reports state that further laboratory-based testing is required prior to field testing.

Another recent report by the US National Academies, “Preparing for Future Products of Biotechnology” identifies over 50 examples of biotechnology products likely to emerge in the next 5-10 years, including those being developed using synthetic biology methods.  The examples include engineered microbes and microbial products, plants, and animals; many are being designed for open release in the environment, others for contained use. 

This report addresses the topic we are now discussing from a different direction, but to a similar end.  By examining examples of the types of products likely to emerge, it recommends a series of measures for the US regulatory system so that one can avoid the “potential negative impacts, including unexpected and significant adverse effects” that Casper has asked us to identify.  Andrew Roberts [#8410] cautioned us to “avoid sweeping generalizations” and focus on specific cases.  I would add to that, not only should we focus on risks from specific cases, but in addition consider what risks might remain after careful testing and review by our regulatory systems.  It is that combination that will allow society to both 1) benefit from the products developed using synthetic biology methods and 2) avoid potential adverse effects on biodiversity.

I am Jack Heinemann, a professor of genetics at the University of Canterbury. This is my first intervention in the forum so I would like to thank our moderator, and acknowledge with gratitude those who have posted before me.

1)

This question does not ask for impacts unique to syn bio, but ones from syn bio relevant to the three objectives of the Convention. Syn bio further develops modern biotechnologies in multiple ways but the area I will post on is how it develops the ‘manufacture and/or modification of…systems.’

I perceive ‘manufacture’ to include the ability to synthesise large nucleic acid molecules, or large numbers of nucleic acid molecules of any given number of subunits, or assembly of synthesized nucleic acid molecules into functional arrays (eg, chromosomes). The effect of advances on synthesis can result in assembly of materials and/or organisms using genetic material (and its sequencing) or sequence information (eg, in electronic form) transferred from one place to another.

While there are multiple impacts on biodiversity that might arise from such manufacture, I highlight impacts on fair and equitable sharing of benefits arising out of the utilization of the underlying genetic resources that have been used in the manufacturing process.

For example, based on the nucleotide sequence of nucleic acids isolated from the environment of one country (“A”), a company in another might manufacture genetic material capable of conferring an economically valuable new organism in another. Through a combination of adjustments to the manufacturing process, it might be difficult if not impossible to prove that the source of the information was a genetic resource of Country A. This could be achieved by assembly of functional units in different but still biologically operative order, use of synonymous codons or substitution of similar amino acids.

In addition, scaling up the capacity to manufacture could also result in the synthesis of nucleic acids based on computational methods rather than biological sources per se. These origins would potentially create new challenges for a risk assessment. For example, Annex III of the Protocol, point 9(b) helps the assessment by knowledge of the context in which the source genetic material exists. This information would be unavailable. For that and other reasons, step 8(a-b) would contribute a high uncertainty to the assessment particularly for “unexpected and significant impacts”.

3)

I would argue that developments in the ability to introduce nucleic acids (or other important tools for syn bio) into organisms in situ, that is, in the environment as opposed to in the lab and then for latter release into the environment, are recent and deserve discussion. To better illustrate by example:

There are in pre-commercial development pesticides based on double stranded RNA active ingredients. Synthesised RNA molecules may be coupled with some vehicle that carries them into cells (across surfaces such as waxy layers). These advances are not necessarily limited to nucleic acids but likely could be vehicles for proteins, too. The uptake of these RNAs may be intended to lead to changes in gene expression or heritable modifications (eg RdDM) in a single recipient, or coordination of biological systems through simultaneous manipulation of multiple target organisms in an exposed ecosystem.

With best regards to all
Jack

Dear experts
I guess you are all aware on the experiment that have been conducted on the Tetiaroa island (Pacific ocean) by Institut Louis Mallarmé, releasing several millions of mosquitos carrying Wolbachia. The experiment has lasted 13 months and is over since 8 months. It had triggered a decrease of the population of mosquitos on the island of (said the project leader) 99.99%, better than the 90% they were expected. This decrease is so far sustainable (8 months since it happens). A residual population remains (0.01%) so mosquitos on this island are not extinct indeed. Yet, one could wonder what is the impact of such a drastic reduction on food webs, other species, shift in preys, etc. but on this island, there are no bats, or insect-eating birds (if I understood well), and mosquitoes are causing problems on endangered marine birds (who may do better now with much fewer mosquitoes). It is also recalled that Aedes polysiniensis and Aedes aegyptii are invasive (naughty) species that were not present in the old times on such islands.

Dear Colleagues,
I am Freddy Bulubulu, Scientist at Commissariat Général à l’Energie Atomique/DRC. Many of the applications of synthetic biology aim at developing more efficient and effective ways to respond to challenges associated with bioenergy, environment, wildlife, agriculture, health and chemical production. However, synthetic biology develops. Many new techniques are being developed around the world in the field of synbio. What are these new technologies? What would be their probable  impact on biodiversity? Many things have been said through this forum, I especially appreciate and I agree the interventions of this morning which are concrete by the citation of some of these techniques as well as experiences that are being carried out.
Thank you.

Dear Participants,

My name is Mark Q. Benedict from the Centers for Disease Control and Prevention (CDC) in Atlanta, USA. I have worked in mosquito biology for my entire career and was a lead author developing the Arthropod Containment Guidelines which have served as a basis for various national guidelines for both disease vectors and transgenic mosquitoes.

Recently, I and 9 other authors have completed a manuscript (accepted) containing recommendations for containment of arthropods containing ‘gene drive’ systems that can spread from low frequency introductions. In contrast to the recommendation of Mr. Hammond ([#8431]) to automatically escalate containment to P3 or equivalent, we observe that containment measures at ‘level 3’ are generally designed specifically for containment of microorganisms by means such as highly regulated air pressures, HEPA filtration and in some cases glove boxes. Some of these measures are actually counterproductive to containment of arthropods.

While we do make recommendations that are not usually specified at level 2, the implementation of many level 3 containment measures would achieve little or nothing to contain gene drive systems. Moreover, the cost would put research into such systems out of reach for many resource-limited countries for which the potential solutions which might result from gene drive are most needed.

I strongly advise against quickly adopting what may appear to be a reasonable precaution, but which does not consider the location of the research being conducted, the effectiveness of the measures being recommended, and the specific phenotype being conferred. As many others have noted, the case-by-case approach is prudent, as are the effectiveness of specific containment measures.

Thank you for considering these thoughts.

Mark Q. Benedict

On Containment

Mr Hammond (Third World Network, #8431) argued that gene drive mosquitoes are “pathogens or pathogen-like organisms” and that any such organisms “designed to harm…wild populations” require “P3 (BSL-3) or higher containment”. 

Pathogens are viruses, bacteria or other microorganisms that causes infection or disease; mosquitoes - engineered or otherwise - are not pathogens.  “pathogen-like” is an undefined term that I do not find helpful in this context.

Definitions notwithstanding, what is an appropriate level of containment for such mosquitoes?  Practitioners and others have thought extensively about this issue, see for example [1] and references in other posts, e.g. #8439, #8447.  Furthermore, scientists, clinicians and others have long experience of handling biological agents with potentially harmful effects on human health or the environment - think pathogens of humans, animals and/or plants, exotic/invasive species, etc, which provides precedent and context for such deliberations.  In particular, a useful analogy may be draw with exotic species being considered as potential biocontrol agents (e.g. predators and parastoids); though not identical cases there are many similarities.  My further comments below are not intended as any substitute for this detail, or appropriate case-by-case analysis, but may help with consideration of some specific issues.

Returning to the classic definition of risk = exposure x hazard

Hazard: 
Any impact (positive or negative) on wild populations will occur only through mating between the synbio mosquitoes and wild individuals.  What happens after that depends on the nature of the synbio modification; for a functional gene drive the modification may start to increase in frequency in the receiving population (depending on various features of the design, e.g. frequency-dependence).  While extensive spread may be the long-term intention, and with significant human benefit (Mr Thomas, #8437 notes that these are “optimum use cases”), for this to occur inadvertently as a consequence of “contained-use” would be undesirable. 

Mr Thomas also asked “Will MCR/gene drives even work?”  Perhaps fortunately, it is becoming clear that the answer is “not easily”, at least for simple CRISPR/Cas9 homing-based designs.  Recent studies have highlighted the sensitivity to variation in the target sequence, the very high level of pre-existing variation [2] and the propensity of the system to stimulate the de novo appearance of cut-resistant sequence variants [3].  The consequence of this is that simple designs will not spread to fixation in wild populations [4], or even laboratory ones [3]; rather they will be eliminated from the population over time.  While I am confident that more sophisticated variants of these designs will have more staying power, this means that published systems would have limited impact on [large] wild populations following any inadvertent release (escape from containment).  Inadvertent release of such a strain would still be highly undesirable, possibly with observable ecological effects, but predictions of cataclysmic consequences are unwarranted.

Exposure:
To reiterate, any impact (positive or negative) on wild populations will occur only through mating between the synbio mosquitoes and wild individuals.  Where the contained-use facility is hundreds or thousands of kilometres from the nearest wild population of the target species, or environmental conditions permitting establishment, the possibility of such impact is a priori likely negligible or zero.  With a few other obvious prerequisites (e.g. the synbio mosquitoes are not themselves infected with malaria/dengue/etc)  such work might therefore responsibly be conducted at ACL-1, though in practice I understand such experimental facilities more commonly operate at ACL-2 [containment levels have different names in different countries and for different purposes - ACL here is Arthropod Containment Level analogous to Biosafety Level (BSL) for pathogens]

This situation would differ for contained-use in locations where the host species is endemic, as the possibility of initial gene introgression into wild populations following inadvertent release would obviously then significant.  In that case I do find some sympathy for the earlier assertion [#8431] of a need for rather comprehensive containment, though again very much on a case-by-case basis.  In practice a great deal of the work needed prior to deliberate release, perhaps including semi-field and/or pilot field studies as well as contained-use, could safely be done with system components.

This is by no means an attempt at a comprehensive risk assessment, rather I have tried to outline some pertinent issues and consider their implications for appropriate containment levels.

[1] Akbari, O. S., et al. (2015). "Safeguarding gene drive experiments in the laboratory." Science 349(6251): 927-929 http://science.sciencemag.org/content/349/6251/927
[2] http://www.biorxiv.org/content/early/2016/12/22/096289
[3] http://www.biorxiv.org/content/early/2017/06/12/149005
[4] Marshall, J. M., et al. (2017). "Overcoming evolved resistance to population-suppressing homing-based gene drives." Scientific Reports 7(1): 377

Briefly with respect to the replies of Mr. Alphey and Mr. Benedict to my last post [#8431]]:  Whereas #8431 is in specific reference to Target Malaria's plan to conduct R&D in the Sahel with experimental gene drive systems designed to eradicate mosquito populations, both Alphey and Benedict's replies are far more generic in their scope of reference. "Mosquitoes with gene drive systems" is not the same as "Mosquitoes with experimental gene drive systems purposely designed to eradicate a target species over a large area."  As others have observed, specifics count.

Dear Members
I appreciate and support the views registered by Mr.Edward
#8461 – very much true. Supporting your views.
#8437 – very good suggestion to list under the following
Developments in Tools and Techniques
Developments in Applications
Developments in Systems, Platforms and approaches
We may add
1. Impacts and releases- as it has already reached the society
2. subject area based approach – most of the time the discussion was about vector control, biofuel and microbes. We are yet to open the major agriculture and medicine
India cannot forget the ban of three GMO crop varieties in 2005 due to its failure in farmer’s fields. What we observed in confined experimental unit may not be enough to prove a technology safe and beneficial. That doesn’t mean that I’m against the technology in total. I mean, we are not yet ready to go for field release of GMO’s at least in the field of edible food crops. We should take some more time to test them thoroughly and case by case with a “BIG NO” to STERILITY GENES AND RESISTANCE GENES MARKERS in edible crops.
1. Expanded gene editing techniques – may be suitable for organisms with small genome. Getting unique single copy gene sequence is a tricky difficulty thing in larger genomes especially plants with lot of repeat regions and “non-coding” feedback/ competitive regulations. 
2. There are already reports of whole genome synthesis – but we need to regulate this as deadly pathogens can be generated or regenerated using this!
3. Editing techniques will add to diversity but how far the beneficial phenotypes are generated is based on the researcher
Not just editing techniques even conventional mutagens to generate efficient variations of any subjected population

Regarding big data, sequences and other data sources my question is how far ABS is going to help those generate them. We may discuss later on this and bio-piracy.

(redesign of nature and the job of policing bio-safety) – I’m totally against to the term “redesign of nature”. Synthetic biology modifies an organism with a new gene which is again present in the nature. We are just manipulating and rearranging. There is nothing to redesign. It's just “Genetic manipulation”.

thanks

Ms. Delphine,
People die due to disease causing pathogens not by vectors. If you eliminate one vector, then the pathogen may spread by some other means or some other vectors. It will evolve a mechanism of spread and its own survival. Hence, if vector eradication is the only solution we should be prepared to eradicate one by one at the end only man will be standing in this earth.
Just like how simple measures bring the endangered to pest list, in the reverse any pest will become endangered by simple control measures. We may go for vector control in serious issues but with a “BIG NO” to STERILITY GENES AND RESISTANCE GENES MARKERS.
thanks

Dear Mr. Vogel,

Thanks a lot for this detailed explanation.

Dear Mr.Luke

Impacts of a species eradication or decline its population on food chain and ecosystem will reflect after long time. It may not be visible within a decade.

thanks

Dear Yeshima.
I appreciate your concern about the conservation of biodiversity. However, I have to point out that vector control has been immensely successful in controlling many vector-borne diseases, including malaria, and in no cases at all the parasite has evaded the control by inventing another form of transmission. Your idea is neither based on science nor in the long experience in the control of vector-born diseases.
Moreover, nobody is suggesting eradicating a large set of vectors, only Anopheles gambiae is the target. And finally, the final strain of gene drive mosquito is not yet developed, many improvements may be added in the next years and they will not involve synthetic biology at all, except if you broaden the definition in such a way as to encompass all new gene modification technologies, what is plainly wrong.
Yours.

Dear members,
I request views on these published literature from experts in the area of vector control “insect vectors involving in mechanical transmission pathogens”, “Mechanical transmission of pathogenic microbes by insect vectors”. “emerging infectious diseases: threats to human health and global stability”.
I may please be permitted to request the opinion from vector control experts on these hypothetical quote “all diseases and their vectors are completely explored and there may not be any new vector to transmit the known diseases”
“insects represents 90% of the total diversity among animal kingdom”
“all probable insects vectors are studied already”

list of mosquito species transmitting different serious diseases
Aedes(Chikungunya, Dengue fever, Rift Valley fever, Yellow fever, Zika); Anopheles(Malaria); Culex (Japanese encephalitis, Lymphatic filariasis, West Nile fever)
Now only one is being discussed here. Don’t we plan to eradicate all these diseases if not now in near future?
Shall we move from mosquitoes .. once these questions are answered
thanks

Dear Yeshima.

Mechanical transmission of diseases by arthropods is not uncommon, but it was never reported for any Plasmodium species. Please consult https://www.researchgate.net/profile/Lane_Foil2/publication/279377186_Medical_Entomology/links/5760433308ae244d0370ca33/Medical-Entomology.pdf .

Moreover, vectors involved in the transmission of human and livestock diseases are very much studied and well known and it is highly improbable that important new vectors emerge, even if the main vector is eradicated. This was the case of yellow fever in Brazil and in other countries, for example. The relevant literature can be found in any good compendium of medical entomology.

Dear members,

I wish to register that, still many of the questions are left unanswered here.
New emerging diseases and pathogens are reported regularly. We are not against malaria control. Please destroy those mosquitoes spreading the disease as an immediate measure.

The genus of causative organism is so diverse, comprising 250 species, 16 subgenera and almost 29 diverse host ranges. Now we are targeting only one of the hosts that too it’s only one species. Obviously a person bothered about biodiversity and ecological balance will raise this question. “Why researchers are not targeting the pathogens to eradicate?”

We are bothered about the way it is being controlled now. Complete eradication of any species though it’s a vector is a very serious concern though there are contradicting reports. We don’t bother if you destroy the pathogen/parasite/pest whatever causes a serious deadly disease to a food crop or human. This should not be an example in near future to destroy any other species. “Why synbio researchers are not working to destroy the pathogen?” is my question. Before the vector is completely eliminated, the pathogen control is to be made available. Researchers could study their phylogeny; they could identify the species and their evolution and the rate of evolution too. Still there are new species or races, whatever may be, left unidentified due to its minor differences indicating their evolution. But they are not destroying them!

Organisms of minor importance to human also deserve to survive in this world and they do have underrated roles in this ecosystem. Eg. Birds, worms, insects… whatever it may be. In general, pathogen eradication is the only solution, vector control is transitory.

thanks

Dear all,

While the moderator has invited us to focus on specific questions, I wanted to propose some answers to specific questions raised about the potential use of gene drive for vector control of malaria transmitting mosquitoes, hoping to bring some clarifications and helping us moving on.

In response to the questions raised by Ms J.Yasin in her post #8470, there is a general consensus within the malaria sector that malaria elimination will require a combination of strategy: reducing mosquito vector population, addressing the human reservoir for parasite, and improving the diagnostic and the case management. The past history of malaria control and elimination has shown that only a combination of different strategies can achieve elimination (see the recent case study of Sri Lanka successful elimination). The recent WHO publication on malaria elimination is very useful to understand this: http://www.who.int/malaria/publications/atoz/9789241511988/en/
This illustrates the importance to target the vector as well as the parasite as in the case of malaria the transmission of the parasite from one human to another one requires the action of a mosquito vector. I hope this addresses the question from post #8467 and #8479

Target Malaria, together with many other research projects, is working on the first part of this strategy which is to target the mosquito vector population. WHO has called for new tools in this recent publication acknowledging the limits of existing tools:

"While factors that may limit the effectiveness of existing vector control interventions must be addressed, even full implementation of core interventions cannot halt malaria parasite transmission in all settings. Evidence from various areas indicates that residual malaria parasite transmission occurs even with good access to and use of ITNs/LLINs or well-implemented IRS, as well as in situations where ITN/LLIN use or IRS are not practical. The behaviour of both humans and vectors is responsible for residual transmission, such as when people live in or visit forest areas or do not sleep in protected houses or when local mosquito vector species have one or more characteristics that allow them to avoid the IRS and ITN/LLIN intervention tools.

Our non-for-profit consortium is one of the group working on trying to develop a new vector control strategy for malaria using gene drive mechanisms. There are two different ways to use this: either trying to reduce the number of mosquitoes from key vector species (usually called suppression or reduction strategy), or trying to make existing vectors unable to carry/transmit the parasite (usually called replacement or alteration strategy). In both cases the aim is to disrupt the cycle of parasite transmission to - in conjunction with other strategies - reach elimination. The aim is not eradication of mosquito species but eradication of malaria so an interruption of the transmission cycle is sufficient.

On the question about other vector species and other parasites/pathogens, Anopheles gambiae is also a vector of filariasis so the reduction in their number should also impact the transmission of that disease. I know there are other groups focusing on Aedes species transmitting several diseases (Zika virus, Dengue, etc.). Malaria is usually the focus of discussion because that's where the research is the most advanced and the need pressing because of its mortality.

I would like to highlight and support the point made by Robert Friedman in #8435 regarding the Vector Control Advisory Group that reviewed both approaches to vector control using gene drive and concluded  "While recognizing the many challenges that lie ahead, VCAG encourages further development of tools utilizing gene-drive based technologies. In this case, gene-drive for spread of malaria-refractory genes. This submission requires more evidence from laboratory-based studies before field testing should be undertaken." http://apps.who.int/iris/bitstream/10665/255824/1/WHO-HTM-NTD-VEM-2017.02-eng.pdf?ua=1

In the case of our project - and as far as I know of other groups looking at using gene drive mechanisms - the assertion "Mosquitoes with experimental gene drive systems purposely designed to eradicate a target species over a large area" (post #8458) is incorrect. We aim at co-developing and share new, cost-effective and sustainable genetic technologies to modify mosquitoes and reduce malaria transmission. In addition, our testing plan is to ensure that this research is done in a responsible manner and that all appropriate risk assessments and regulatory reviews have been done prior to any import to endemic country or field evaluation. As highlighted by VCAG and other groups, we are very aware that more research is needed before anything is testing in the field and welcome stakeholders' inputs (such as through this online forum) in the hazard identification as well as stringent risk assessment process and a benefit/risk analysis.

As an example of such process, we welcome the analysis that was done last year during a workshop specifically trying to identify potential hazards and thoroughly reviewing potential pathway to harm. The results of that workshop can be found here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361523/
Similar activities are currently being promoted by NEPAD - the New Partnership for African Development - aiming at co-developing this technology with African countries and ensuring that stakeholders' voices have been expressed and taken into account.

To conclude - and my apologies for a long input - I would like to reiterate points made by several people that this technology is still at a very early stage of development, in the lab and requires improvements and further studies. Nobody is proposing to release those before complete case-by-case review and regulatory assessments.

POSTED ON BEHALF OF SURESH SUBRAMANI
-------------------------------------------------
I concur with  Ethan Bier and Andrew Roberts regarding their view that risk assessment should be dealt with in a case and context-specific manner.

POSTED ON BEHALF OF PETER KWAPONG
------------------------------------------------
Mr Taye,
Your point is well noted
Peter

Hello

I am Carlos Augusto Ospina Bravo, I am Biologist, Ms.C in Microbiology, I work as a professional specialized in the Ministry of Environment and Sustainable Development of Colombia.

Following the topic of discussion of topic 1.

Taking into account that there is still no clarity on the adverse effects that developments derived from synthetic biology can have, because it is a complex and recent area, it is possible to make an analysis of what has been developed and to think about the possible effects that could Have for biodiversity, some of the negative effects could be:

• If the production of applications in synthetic biology expands significantly, both intentional and involuntary environmental impacts could be important. For example, the production of biofuels.

• Possible future applications of synthetic biology that could be beneficial to the conservation and sustainable use of biological diversity, such as microorganisms designed for bioremediation, to improve agricultural efficiency, to stop desertification, to cure wildlife diseases, Etc., would require the release into the environment of micro-organisms resulting from synthetic biology techniques.

Dear colleagues,

Thank you Casper for accepting the challenge of moderating this discussion and thanks to the Secretariat for compiling the information presented in the supporting document. My name is Sarah Agapito, I am a plant biologist at GenØk Center for Biosafety in Norway (the national competence center in biosafety) and also an adviser to the Brazilian Government. We have already lectured two international courses on biosafety aspects of synbio and also wrote two reports on knowledge gaps in synbio and new techniques. The main goal of my research is to uncover the roles of transgenes and CRISPR mutations in gene regulation in plant systems and to apply that knowledge to assessing their safe use in food and the environment.

I would like to contribute to the discussion by following the task that has been given to us and thus reply to the guiding questions below.

Question 1) Re. potential negative impacts
As mentioned by the moderator and other colleagues, synthetic nucleases, such as the CRISPR-Cas system for genome editing, are one of the most promising and powerful supporting techniques in synthetic biology. However, these systems still lack fundamental knowledge about their functioning and safety. Biosafety concerns have been raised regarding their potential to cause off-target mutations, or mutations in genomic sites other then the intended site. Off-target mutations can be hard to detect due to the possibility of small deletions/insertions. On the other hand, even small changes in genomic sequence can lead to significant alterations in gene regulation, protein contend and, consequently, metabolic disturbance. Unintended changes in synbio organisms and components can be harmful to organisms exposed to them. Kinetics of such nucleases and mutation stability are also of concern and long-term studies have yet not been performed in vivo, especially in the field of plant biology.

Question 2) Re. research on potential negative impacts
We have started a small pilot project on plasticity of plant cells that have been genome edited, and how they can cope with such interventions, focusing on CRISPR off-target activity (http://genok.no/the-synplast-project/). I am not aware of research exclusively dedicated to biosafety aspects of synbio. Usually, research is dedicated to the development of products, which might include a safety analysis.

Question 3) Re. other relevant technological developments
Genome editing techniques, which do not include a template DNA (and thus based on non-homologous end joining), as well as CRISPR nickase systems, should be carefully considered in this discussion because of the challenges related to their detection and identification and also risk assessment.

Best regards,

Sarah Agapito

Taking as reference the reports of the convention of biological diversity on the discussions that have occurred around the biology of the environment, it can be established that the biology presents a series of benefits and technological developments, however these developments can lead to possible negative effects to the environment And biodivesity as they are:

- The transfer of genetic material from microbes which were produced through synthetic biology
and released into the environment, to other microorganisms could have unforeseeable
consequences;
- The use of “gene drive” systems to spread traits aimed at suppressing populations of disease
vectors (such as mosquitoes) could lead to the introduction of new diseases through the
replacement of the population of the original disease vector by another vector species;
- Possible toxic and other negative effects on non-target organisms, such as soil microorganisms,
beneficial insects, other animals and plants;
- Potential negative impacts to the conservation and sustainable use of biodiversity could arise from the transfer of genetic material to wild populations via vertical gene transfer and introgression.

Synthetic biology is a great opportunity for innovation and development, every day it takes more strength, it is important to generate the necessary instruments to allow its development to be carried out in a controlled and sustainable way, since at this moment we are not sure of what are its environmental impacts And biodiversity.

This is also on the  issues raised by Carlos about the use of “gene drive” systems to spread traits aimed at suppressing populations of disease vectors (such as mosquitoes) could lead to the introduction of new diseases.

We understand the objective is to suppress the receptor protein responsible for the completion of the malaria cycle. However, one might ask what about the both knock-out and knock-in effect. This means the genetic makeup of the organism is also changed. What might lead to this changes in this genetic make-up that might affect other signalling pathways of the organism metabolism. What will those effects lead in terms of diseases or pathogens, behavioural changes that can affect the ecosystem services. Are there confined studies carried out by far on the effect of CRISPR/Cas 9 on currently been done its effect on ecosystems.

Greetings to all

I am Dr. Jean Bruno MIKISSA, I am Lecturer at Ecole Nationale Eaux et Forêts of Gabon, I am Catagena National Focal Point and I conducted the Biosafety project in my Country. As this is my first post, I would like thanks all my colleagues for their good contributions. Sorry to join late the forum due to my work in the field. Just I want share the point of view rise by Mothalepula. It is important to take into account the Cartagena protocol issues and Invasive Alien Species.

Thanks

Jean Bruno MIKISSA

Dear All,
I am v grateful to participate in this discussion and thank everyone for their interesting insights. My name is Eva Sirinathsinghji and I work on biosafety issues of GMOs and pesticides in agriculture.

I have a couple of points to make regarding the potential negative impacts to biodiversity and regulation of new techniques.
Off target effects of gene editing technologies and RNA technologies:
- RNAs have recently been shown to survive mammalian digestion. They have also recently been shown to have cross-kingdom regulatory capacity, with experiments now validated in numerous studies. Regulatory RNAs from foods are now understood to be able to regulate human genes following consumption.  We also know that predictive off-target effects of regulatory dsRNAs by bioinformatics are not sufficiently reliable.  The introduction of synthetic RNAs into the environment could therefore have unintended effects on non-target organisms including humans.
- Large-scale off-target effects of CRISPR was recently highlighted in both a mammalian study in mice, as well as in plants where there were over 100 mutations include large-scale deletions and insertions of genetic material as well as integrations of the vector backbone.

This brings me to my second issue with regards to regulation of new techniques for LMOs. Some of the above effects are related to the technique themselves and highlight the need to continue with the definition of an LMO as one involving the use of biotechnological techniques. I have seen a couple of comments on the thread suggesting a move towards defining an LMO by the product and not the modification technique. Such a move would ignore the inherent risks of these techniques, some of which are identical to standard LMOs. The suggestion that the genetic variation introduced is nothing more than natural variation ignores the above findings of large-scale rearrangements, vector integration into the genomes, all of which were only discovered following thorough genome-wide analyses currently not required in RA for LMOs.
Many risks relating to current LMOs have already materialised, highlighting the continued need to define an LMO by its technique and not just the final product. Any relaxation of this definition could lead to lack of RA, labelling and monitoring. Regulation might instead, be best modified and updated to take into account novel risks introduced by new techniques. For example, the inclusion of “omics” technologies for thorough global screening of disruptions to at DNA/RNA/protein/metabolite level could assist in picking up unintended effects.

Lastly, the issue of benefits sharing and biopiracy is a big concern. I support the moves to treat digital sequence information as physical biodiversity samples.

Hello every one!!
Most of you have well noted the negative impacts on mosquitoes arising from genome editing. It is good to see CRISPR-Cas9 gene drive system targeting female reproduction in the malaria mosquito reducing the reproductive capability of the insect vector. As a result, it has direct negative influence on anopheles mosquito population. In my opinion, this is either gene knock out or knock in. therefore, unless there exists insertion of synthetic genes along with the nuclease, this case fall within the scope of legislation regulating genetically modified organisms (GMOs).

On the other hand, there are indirect impacts on biodiversity arising from synthetic metabolic engineering. Organic chemical synthesis through synthetic metabolic engineering may have impact on biodiversity, for example in 1.3 propanediol production  the engineered species is switched off to use the substrate glycerol and switched on to use hexoses like sugar that may have consequence on the environment. Here off target and non-target cases couldn’t work because it is competition for nutrient.

Re off target effects (#8504): The  work of Schafer et al in mice published earlier this year (https://www.nature.com/nmeth/journal/v14/n6/full/nmeth.4293.html) is being used as an exemplar of extensive off target-effects with current CRISPR-Cas9 methods. However, the interpretation of these data have been called into question due to limitations in the experimental design (http://www.biorxiv.org/content/biorxiv/early/2017/06/21/153338.full.pdf). In addition, there are considerable efforts aimed at developing more specific nucleases, i.e. work from the Dudna lab published this week shows how Cas9 specificity may be increased (http://www.biorxiv.org/content/early/2017/07/06/160036).

The fact that CRISPR relies on the endogenous repair mechanisms of the cell opens up the process to unpredictable genomic DNA edits that can result in large-scale deletions and insertions. This is part and parcel of the technology as it currently stands, even acknowledged and taken advantage of by companies such as DuPont who recently gained licencing agreements of the technology and are heavily invested in it. They published a recent Nature Methods paper in the issue: Mapping the genomic landscape of CRISPR–Cas9 cleavage. Again, such side effects of the technique implies inherent risk of gene editing, and thus would be appropriate for them to fall under the current definition of an LMO.

The efforts to discredit that mouse CRISPR paper is largely predictable. I can also point to the authors' response to such critiques. There are however, multiple studies regarding off-target effects and development of techniques for their detection, a few recently published (Nat Biotech 33, 822; Nature Biotech 33, 1679; Nat Methods 12, 237) One of those even detected chromosomal translocations.  Some of these studies report that they can reduce off-target effects substantially, but we are not at the stage of guaranteeing lack of off-target effects by any means.

I have read with the interest the latest comments and citations on CRISPr off-target effects and how these might affect biodiversity in released applications. It is well documented that using CRISPr gene editing can produce off-target effects and many researchers are working to reduce these.

However to balance the discussion a little I would like to offer an observation. i note that natural breeding programs including farm and fruit products produces a series of genetic alterations which are unknown. I was surprised to learn (please correct  me if I am wrong) that products from 'natural' breeding methods do not have to have their genomes sequenced as part of current regulatory structures. In fact i was slightly taken aback when i looked into shop sold strawberries as a useful source for extracting DNA for school  teaching or public  demos. It turns out that wild strawberries contain 7 pairs of chromosomes and a genome size of 206 million base pairs and 34,809 predicted genes.  Cultivated strawberries (which are often up to 10x size of wild strawberries) are estimated to have 8 lots of 7 chromosomes and a total of 56 chromosomes (polypoidy). The genomes sequences of these cultivars is unavailable as it any of the genetic changes which have resulted in the large sweet and delicious strawberries we buy. Do natural cultivars affect biodiversity and if so does anyone have any exemplars they can share?

I am a little perplexed about the arguments against rationale often knowledge based targetting of genetic changes using new tools like CRISPr for specific purposes. If we do not know what  the genetic variations we have introduced into what we call 'natural' organic products though 'natural' breeding/cultivation methods then why are we so  against rationale genetic engineering.

My name is Toni Piaggio, I am a wildlife geneticist with the US federal govt. I am pleased to see all sides of these issues presented. I did want to be sure that we all had the latest research on the topics to work from. This week a paper by Lareau et al. was put out (not peer-reviewed yet however) that demonstrated that the previous work by Schaefer et al. (2017) that was based on looking at CRISPR-Cas9 editing across the genome of 3 mice (with a single control mouse) and put forth that many unexpected changes occurred across the genome was likely due to the close genetic relatedness of the two mice relative to the single control mouse, which was from a different lineage. The Lareau paper argues that the mice must be genetically identical to start in order to be able to show changes are due to the gene editing rather than natural mutations not shared between the lineages before the editing occurred.

I agree that crops derived from unregulated techniques such as mutational breeding (which was largely inefficient at generating useful crops) should also be regulated and screened at the genomic level (and higher levels), as should GMO crops which currently do not require whole genome sequencing for RA.
However, I disagree with the idea that CRISPR and other gene edited products are no different to other conventionally bred crops, whose natural variation is based on allelic differences that have survived natural selection for many years. This is a natural mechanism operating on the level of the DNA to generate diversity within a species, yet at the same time preserve the integrity of the genome with letter-by-letter exactness.

I struggle with 1) the concept that gene editing is precise, when the side effects are well understood, and 2) the concept that CRISPR is both novel, and also as good as natural, and thus can be declared to have history of safe use. It cant be both. It must be thoroughly tested, and until full profiling techniques that analyse global gene/mRNA/ncRNA/protein/metabolite profiling, the claim that this tool is precise is rather based on assumption and faith, and not evidence-based science. It seems highly unlikely that precision and detection methods can reach a level where off-target effects can be confirmed to be absent.  Regulation in this case, should be stringent if we are to follow the CBP's precautionary principle.

The same issue of off-target applies to RNA species also. Some crops and sprays are now on the market in the US, without testing of off-target effects. We are seeing in the literature that RNA epigenetic effects can even be inherited in certain cases, another aspect that could have long term effects on biodiversity. The fact that plant ncRNAs have modifications that make them highly stable (unlike mRNAs) means that risk of exposure is far greater than has been previously assumed.

Dear Members,

The discussion is going great now.  I will try to answer Mr.Paul’s questions.
1. Any variation added to the pool actually increases diversity. (Provided it is not containing any deleterious genes)
2. Polyploidy is generated in nature as well as by artificial means of inducing mutants
3. Polyploidy may or may not be crossable in any plant species with a diploid as it creates imbalance and partial synteny during cell division
4. Strawberries (as well as many of the polyploids are) vegetatively propagated. So any adjacent GMO or LMO cannot directly affect them through pollen contamination
5. Natural cultivars are the members of biodiversity; they effect biodiversity
6. Not just natural breeding, even MAS or any basic tool in biotechnology based breeding doesn’t require the whole genome, but CRISPR needs to identify the unique target. Identifying unique targets in larger genomes are highly tricky as I mentioned already

What nature introduced in the form of a mutant or a polyploidy don’t have any deleterious gene which is autokilling by nature to destroy its own genome. Infact those naturally introduced variations are of “selfish” in nature to perpetuate. But what we introduce is against natural selection and it affects the other organisms too.

I hope my answers are enough to clear the question.

thanks

Dear all

By following the discussions, I still retaliate  that synthetic biology systems just like any other GM techniques should be treated as LMOs, since both technologies   in my opinion result into an LMOs or their products. Again biodiversity issues that have been raised since the onset of this discussion are  covered under  CPB, hence  synthetic biology systems is of no exceptions.

On the other hand,  stringent measures against synthetic biology systems cannot be of good to innovations on addressing problematic issues in life. We should also take into account substantial equivalence measures on the technology versus what has been occurring naturally,  mutation (radiation), GM technology  as well as their scientifically proven adverse effects  on biodiversity.  I hope you will advice in that regard.

I think our group would like to take a look on this paper…

https://www.nature.com/nature/journal/vaop/ncurrent/full/nature23017.html

All the best,

Joaquim A. Machado

Thank you for the message [#8518] with a link to the 12 July 2017 article in Nature (doi:10.1038/nature23017). The illustrious authors recognize that DNA is a medium of transmission of information in their opening sentences:

“DNA is an excellent medium for archiving data. Recent efforts have illustrated the potential for information storage in DNA using synthesized oligonucleotides assembled in vitro. A relatively unexplored avenue of information storage in DNA is the ability to write information into the genome of a living cell by the addition of nucleotides over time.

Recognition of information as the object of R&D does not exist in the AHTEG definition of synthetic biology.

Dear all

It is pleasing to see the level of activity in this forum and the high standard of civility. But the activity level might mean that I have missed some relevant posts which I apologize for in advance.

In my original post I objected to broadening the focus of Topic 1 to include benefits. Some have responded to this and I've reflected on those responses. I remain though of the position that it is neither helpful nor appropriate to redefine Topic 1 in this way.

1. We have worked hard to develop guidance derived from negotiated text (eg Annex III of the Protocol) for risk assessment. It is not correct that 'benefit analysis' is somehow easier to conduct or less contentious of an issue. What is the standard of evidence for a claim of benefit? We have standards for evidence used in a risk assessment. Moreover, I am still not convinced that the Parties asked for a list of proposed benefits even if the AHTEG has produced some such text on this in the past.

2. There are many legal instruments to address harms of products whether or not they were identified by a risk assessment. In addition, at least some countries have an ongoing expectation of 'duty of care' by product suppliers to identify and address harms should they arise after approval. There is no equivalent framework that would compel a promised benefit to be delivered. The closest instrument that I am aware of is to prosecute for false advertising. But that requires promised benefits to have actually reached the stage of being advertised. They may disappear long before that but still have reached stages that are relevant to risk assessment before they did, or may escape scrutiny in this way altogether.

3. As an extension of this concept has been the suggestion that we should consider the harm of not using a particular product of this technology. I find this also problematic. What are we comparing? Is it harm of the status quo vs the unenforceable and yet to be verified expression of how a new product or technology might reverse or lower that harm? Then do we consider the harm of not realizing a promised benefit? That is especially important if in directing resources to a product or technology a better approach (including from social change) was abandoned or slowed.  Do we consider the harm of the status quo as the baseline, or do we compare benefit claims from different and perhaps incompatible technologies or social practices? In which case would a net benefit to the status quo be a net harm if the other technology/product/approach made better claims?

With best regards
Jack

Dear all

I agree with outcomes from Nature article about the DNA. But, we must keep in mind the fact that, yes all scientists agreed on DNA role, the issue is concerning all stakholders. What is DNA for policies makers or socio-science? In addition others matters appear like climate change. What is the impact of climate change in DNA or mutations resulting? We must analyze carrefully the issue in order to clarify any ambigues, may be that's why parties prefer the terminology "precautionary approach.

Best regards

Jean Bruno

Dear Ms. Motlalepula,
[#8516 -We should also take into account substantial equivalence measures on the technology versus what has been occurring naturally,  mutation (radiation), GM technology  as well as their scientifically proven adverse effects on biodiversity.  I hope you will advice in that regard.]

The first point you raised here is technology vs. naturally occurring variation (may be by mutation) –
for example: in a natural population of any organism there are lot of alterations incorporated every generation; not just by mutation but by so many other mechanisms also which leads to variations generated in progenies. The best one to quote here is the alu elements of human and their exonization. The exonization of these inserted elements causes at least 1000 variations on an average in a generation. If this much is variation is fixed in every generation, the human might have evolved in to something else by this time. But it won’t occur. Because there are other mechanisms of proof reading the genome and checking the validity of inserted new variations. This makes either fixation of a gene / variation or drifting. The best fit will always gets fixed.
On the other hand, we introduce a gene of interest to modify artificially. This alters the interest of the cell. To some extent the modified cell can produce the foreign protein; but may break at any time. This carries negative deleterious genes of nature’s interest and requirement. Based on the dominance nature and its epistatic ability, either the introduced gene may survive or may be silenced or drifted based on the event.

In the later natural event, the variation cab be transmitted to other members of the population without any deleterious effect within and between populations. Hence, the natural events are safe for the environment as well as biodiversity.

thanks

The issue of knowledge gaps seems particularly pertinent with gene drives. Unlike standard GMOs whose environmental release has been controlled, a gene drive's purpose to persist in nature and spread throughout populations raises biosafety risks that cannot be undone once released into the environment (proposals for reverse drives are highly speculative).
Further, I recall discussion earlier in the thread asking for specificity of negative effects of gene drives on biodiversity, though the full ecological and health impacts of gene drives are unknown and likely difficult to predict. The eradication of a single species or altering its behaviour could have a whole manner of downstream effects on symbiotic species/predators, pollinators, food webs, competitor species, and so on. Pathogens and parasites may shift hosts, and new ecological niches opening up. We have seen studies where the control of one mosquito species leads to invasion of another one. We also have the potential, with regards to gene drives and not other vector control systems, of the potential for transfer of gene drives to non-target species, with horizontal gene transfer now recognised as a reality of GMOs.

The gene drives will also be subjected to mutations and evolutionary pressures with potential accumulation of mutations over generations. This can have additional off-target effects beyond the innate off-target activity of CRISPR. What would be the result of these off-target effects in target and non-target species? Altered fitness, behaviour...? ANd the downstream ecological effects? Clear end-points for measurement are not even easy to define and test, especially in controlled settings.

These issues could have serious adverse socio-economic effects in terms of food production. Patents on the crops could also exacerbate threats to economic livelihoods. There are patents to use gene drives to re-introduce herbicide tolerance into resistant weeds, which would only consolidate  agrochemical industry profit and monopoly over food systems and has no positive potential in terms of societal benefit. The organic sector could also be jeopardised by the spread of gene drives. The US military is also a huge funder of gene drives that raises the issue of bioweapons.

We are currently in a situation where knowledge gaps are huge, and gaps in government regulation are the same. There is no effective governance of transboundary movements of gene drives. Currently, the CBD gives nations the right to refuse GMOs, but this is impossible with gene drives.

With such large knowledge and governance gaps and the potential for irreversible effects and lack of containment measures, there is currently a need to call for a moratorium on gene drive technologies under the precautionary principle.

Mr Heinemann’s arguments  but do not find them convincing, being more persuaded by earlier posts drawing the opposite conclusion.  Regarding what we are asked to do, I feel we should continue to advise on “potential impacts”, recognising that these may be positive or negative; this was also the conclusion of our moderator [#8442].  This is important for several reasons, not least that a given action or outcome may be seen by positive as some and negative for others.  While one might imagine that “positive impact on biodiversity” or “negative impact on biodiversity” might be clear-cut, it is evident simply from the discussions so far that this is not the case (e.g. in relation to suppression/elimination of specific mosquito populations, or the impact of sequence variation and mutation).  Furthermore, the impact of a single tool, applied in the same way, may be considered positive or negative in different circumstances, for example the elimination of a problematic invasive pest population (commonly seen as positive) vs the same method and outcome applied to a native population of the same species.  This makes nonsense of sweeping categorisation as “good” or “bad” and again highlights the need for case-by-case analysis rather than sweeping assertions of harm (or benefit).  Several other arguments for including consideration of benefits, or at least not excluding that, have been presented in previous posts.

Mr Heinemann also argues that there are “legal instruments to address harms of products” but not for benefits “The closest instrument that I am aware of is to prosecute for false advertising. But that requires promised benefits to have actually reached the stage of being advertised…”  Harms similarly need to have occurred, so the situation is not as different as Mr Heinemann indicates.  Furthermore, mechanisms for balancing risks and harms are in fact very familiar.  For example in the area of pharmaceutical products - acceptable side effects for an anti-cancer drug are completely different from those of an over-the-counter analgesic, or vaccine, for example, for obvious reasons of balancing potential harms and benefits.  Perhaps closer to the topic of this discussion, environmental impact assessment (EA/EIS) under the US regulatory system (e.g. NEPA) requires an assessment of the proposed action, alongside potential alternative actions and the “no action” alternative, i.e. the current situation.  This is almost exactly the concept that Mr Heinemann attacks in his point 3, yet has been in place for many years.  I’m certainly not suggesting it’s perfect, but unworkable - clearly not.

Thanks for the exciting on-going discussion, it is very instructif.

From my previous post, I mentionned some risks and opportunities of synthetic bilogy on conservation of biological diversity. Altough synthetic biology, view as new technology is not yet really apply in developing countries, these countries especially from Subsaharian Afica and Latin America must not be left behind, because they pocess a huge and diverse diversity, in terms of animal and plants species round the world.

Therefore, there is a need for more careful and inclusive thought about the implications of synthetic biology for biodiversity conservation. There has been a significant effort on the part of the synthetic biology community to explore the ethical and philosophical dimensions of synthetic biology, and to address some of the issues of civic and environmental responsibility and biosecurity.

Indeed, conservation may be affected both positively and negatively by land-use changes associated with the adoption of production systems using organisms developed from synthetic biology techniques. Many of these kinds of impacts already occur, sometimes increased by existing GM (genetic modification) technologies, and it is not clear what additional impact (if any) synthetic biology will have on these processes. Though often framed only in terms of negative consequences involving conversion of land under natural cover and loss of livelihoods, some GM crops (and perhaps future crops modified by synthetic biology) have been shown to provide conservation and livelihood benefits.

In addition, there is the potential for synthetic biology to be used to reduce the impact of human land use on biodiversity and to support ecosystem services. New technologies based on synthetic biology may be able to reduce the ultimate driver of most conservation problems by mitigating the impact of human activities. For example, land and sea habitats that are currently unavailable to wildlife as a result of energy installations could be freed up with new methods of energy production, and the effects of climate change on conservation reduced through large-scale deployments of carbon consuming algae (although these might produce their own knock-on effects).

There is also an enticing prospect that synthetic biology approaches could restore degraded lands and waters for either conservation or for increased food production, potentially sparing wildlands.

For instance, honeybee populations are economically important for the pollination services they provide. In some countries like the northern dried part of my country (Cameroon, Central Africa) populations have declined in association with the colony collapse disorder. The subsequent consequence is the presence of many hectares of unproductive fruit trees (especially mangoes' trees). Hence, synthetic biology techniques could be applied to develop bees that are resistant to pesticides and to mites that prey on bees and that transmit viruses. Such applications of synthetic biology may have great promise .

Happy reading.

Thanks

I have enjoyed and learned from the spirited exchange amongst my colleagues.

I would like to offer another perspective, prompted by the intervention of Ms Eva (8623).

As we consider both costs and benefits (as instructed by our moderator and emphasized by Mr. Luke (8524) we need to consider the points raised in a number of messages over the last couple of days.

As we have learned through the research concerning the Anthropocene, most all parts of the earth and its biodiversity are already impacted by human activity, from the climate to ecosystems, species, and genetic diversity. There is no nature untouched by human hands. It is not as if synbio applications will harm an otherwise pristine genome, species or ecosystem. It is a question of how potential harm/benefit will impact these already impacted systems.

We have learned through the extensive work on invasive species that not all alterations are bad for native species/ecosystems. Some are very, very harmful, some beneficial (consider pollination increases from non-native bees) and probably the majority are neutral in their effects. We have also learned that the loss of some species is highly detrimental to other species but the loss of others has little impact – think of the loss of the American chestnut – once a major forest tree along much of eastern North America whose loss resulted in only minor effects on the whole rest of the ecosystem. We are not dealing with a system in some sort of balance but one in which species like many species of human-commensal mosquitos are already leading ecological lives wrapped around the ways humans have altered the world.

What is clear is that changing things for good or bad as a result of synbio will be contributing to a system that is already undergoing dynamic change. The challenge we all face is how to sort out the signal (the synbio effect) from the noise (the already on-going change) and how to incorporate this knowledge into risk management frameworks and ultimately into policy.

Thank you for your consideration.

Mr Kent Redford - thank you for that perspective - I really appreciate the 'signal to noise' analogy.

A recent post [#8523] proposes a moratorium on gene drive technology due
to uncertainty and gaps in knowledge. I suspect all who are participating in this discussion would agree that gaps in knowledge exist, but the proposed moratorium on gene drive research would ensure that the ‘missing knowledge’ is never obtained and is a simple but self-fulfilling initiative.

As has been repeatedly affirmed, all technologies and their potential outcomes must be evaluated on a case-by-case basis. A moratorium is a blanket dismissal of this time-proven and widely accepted principle.

Mark Benedict

I wish to clarify my previous post that an immediate moratorium on gene drives (applied research, development and release) is appropriate based on a number of reasons, not just gaps in knowledge. We have a huge governance gap in terms of protecting transboundary movements of gene drive organisms. The right of a nation to refuse such technologies is a principle of the Cartagena protocol, which would not cover the uncontrollable gene flow that comes with gene drive organisms. How can a country enact its right to refuse LMOs when the neighbouring country has introduced gene drives?

This is Zach Adelman at Texas A&M University. I wish to echo Mark Benedict's post concerning knowledge gaps that can only be filled through controlled, contained experimentation for gene drive research. This point was the main conclusion of the recent National Academy of Science report "Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values". That is, contained research should continue to fill knowledge gaps. Please keep in mind that the term "gene drive" is not very informative concerning the technology that it is referring too. "gene drive" could mean a CRISPR/Cas9-based system capable of homing through the introduction of a DNA break followed by homology-dependent repair. But it could also mean an underdominant genetic arrangement, perhaps involving transgenic sequences or perhaps a fixed translocation. Each of these systems have been shown experimentally to have very different properties in terms of their ability to spread in laboratory populations, and preliminary modeling suggests very different abilities concerning their ability to spread (or not) in natural populations. Many other synbio-based gene drive systems have been proposed, some experimentally validated in the lab, and no doubt additional systems will be generated that have their own distinct properties. Calling for a moratorium on all gene drive research ignores that fact that technology is extremely diverse.

Well, Mr. Adelman's intervention dovetails perfectly with my previous observation that we need look quite seriously at the novel challenges for laboratory biosafety / containment for gene drive (and some other) synthetic biology organisms, particularly impacts on biodiversity in the event of accidental or unauthorized release. 

Gene drives are obviously transmissible and may - deliberately or accidentally - incorporate genetic material(s) with deleterious effects on natural populations.  This may be of particularly high concern when the species under study (and which could escape) is found in the environment near the facility in question.  There are, in indeed, many interesting parallels to the pathogens that some gene drive organisms resemble.

Certainly recent history has shown serious lapses in lab biosafety and controversies over experiments (e.g. gain-of-function studies in viruses) that give pause to accepting the oversimplified argument that 'more research' is the only answer for managing gene drive research.  Indeed, there may be research that is too dangerous to conduct or that should only be conducted under highly restricted conditions. 

Lab biosafety lapses in recent years such as the release of foot and mouth disease at the Pirbright Institute, the cover-up of lab-acquired human infections at Texas A&M University and subsequent scandal, and the loss (and later finding, under inadequate containment) of viable smallpox by the US Department of Health and Human Services more than amply demonstrates the potential for mistakes causing biodiversity impact at some of the very institutions with persons here that endorse ramped up gene drive experiments.

In my view a moratorium may be reasonably called for, however, at a minimum, the particular and novel challenges that some gene drive experiments and organisms pose to proper contained use, must be identified and addressed at a high level before such experiments advance.  The challenge of doing this is heightened by the knowledge gaps that Eva Sirinathsinghji has pointed out.

Edward Hammond

Following the logic put forth by Mr. Hammon (#8532) would imply the cessation of all laboratory work with infectious agents at BSL4, BSL3, and perhaps even BSL2, in addition to gene drive research. This is unlikely, as each of our nations has understood that the benefits of working with dangerous human pathogens outweighs the risk that these pathogens will escape and potential sicken or even kill bystanders in the surrounding areas. Whether to work with a specific pathogen, and under what conditions, is a decision made by biosafety authorities and governmental agencies on a case-by-case basis. I have yet to see a proper rationale stated in these discussions as to why gene drive technology (which is may be as diverse as the types of pathogens we work on), would require a different framework. Especially considering that gene drives, in all of their forms, pose no threat to the health and safety of laboratory workers or the general population, unlike the dangerous pathogens we already manipulate for societal good.

Mr. Adelman is flatly incorrect and I must say I suspect disingenuous to assert that my logic is for a cessation of all research with any organism at BSL-2 and higher.  The reference here is to contained use of gene drive organisms with known or possible deleterious effects on biodiversity. 

Mr. Adelman may not be aware that for many years there have been classes of experiments that are effectively prohibited in many countries, for example, experiments conferring bacterial resistance to clinically relevant antibiotics. 

More recently, and quite relevant to this discussion on synthetic biology, the US government has imposed a moratorium on so-called gain-of-function experiments with certain pathogens. These include pathogens that are increasingly wholly synthesized in the laboratory, such as influenza, and would fall under our definition of synthetic biology. Indeed, at a technical level, a gain-of-function fully synthesized influenza pathogen may be quite easily constructed by a growing number of labs.

The point with respect to gene drives is that while some organisms with gene drives are pathogen-like in many aspects, as others have pointed out and is obvious, such organisms are not pathogens per se, and the more dangerous among then cannot be entirely assessed using the same Risk Group and Biosafety Level framework that is traditionally applied to disease agents, much of which is developed around the objective of preventing human exposure to a disease-causing organism.  In the case of gene drive organisms, for one example, a primary concern may be that inadvertent release of even a single organism with the functioning gene drive may cause an entire population of the same species to eventually count that gene drive among its genetic material.  This is quite different that the case of human (or for that matter livestock) exposure to a laboratory material.

Several posts have posited a difference between “natural” mutation and sequence variation and such variation induced by synbio methods.  For example Ms Sirinathsinghji (TWN) wrote [#8513] “…I disagree with the idea that CRISPR and other gene edited products are no different to other conventionally bred crops, whose natural variation is based on allelic differences that have survived natural selection for many years”. 

Crop plants have been artificially selected for a range of agronomically-desirable traits.  This comes with significant fitness costs; as a consequence of this, commercial varieties do not typically persist or spread beyond their agricultural area despite very large initial plantings.  Similarly, competition from other plants (“weeds”) needs to be artificially suppressed in order for the crop to flourish.  This is not natural selection - that produced the weedy ancestors from which modern crops have been artificially derived.  Nor is it the case that traditional selection methods do not bring undesirable traits with them, which has been implied in discussion of gene editing.  There are plenty of examples of this in crop plants, but perhaps better-known in dog breeds, many of which suffer from congenital heart disease or other genetic problems.  These traits were not positively selected by dog breeders, but are “based on allelic differences that have survived…for many years” despite being dramatically negative in terms of natural selection.

It is also asserted in earlier posts that CRISPR/Cas9 can cause large-scale (off-target) chromosomal changes and that this makes it qualitatively different from natural variation.  Leaving aside whether CRISPR/Cas9 does indeed cause such changes, and at what rate, none of this is outside the range of spontaneous (“natural”) mutation.  This comprises changes in chromosome number (ploidy), large and small inversions, deletions, translocations etc as well as smaller insertions, deletions, single nucleotide changes and so on.  Countless examples of each of these can readily be found in natural populations.  Natural selection will, indeed, generally prevent maladaptive mutations accumulating to high frequency, but not from occurring and persisting for considerable periods, especially if the maladaptive trait is substantially recessive.

This issue also interacts with gene flow.  Mr Then [#8495] cited a paper indicating that Golden Rice can show undesirable traits when crossed to Swarna, an Indian variety.  He further asserted that following cultivation, “it is likely that the relevant genetic information would have been transferred to weedy rice known to exchange genetic information with cultivated rice. The problematic gene constructs from the weedy rice could then have been passed into regional rice varieties. This sort of geneflow could have a major negative impact on seed biodiversity.”  What level of geneflow is posited?  The assertion is that the trait is significantly deleterious.  In this case, the argument of Ms Sirinathsinghji and others, that natural selection will rapidly eliminate the trait, is correct.  Geneflow from cultivated to weedy rice, and from there to “regional rice varieties” would have to be occurring at an implausibly high rate to maintain the trait at any significant level - and if it were, all the other less deleterious alleles would be more efficiently introgressed; in short there would be no recognisable “regional rice varieties” as they would have been homogenised by gene flow from conventional cultivated rice.  Assertions of potential harm to biodiversity from intended or off-target effects need to carefully consider issues of selection and gene flow in quantitative as well as qualitative terms.

Mr Hammond’s personal attack in his reply [#8538] to Mr Adelman [#8536] is entirely unwarranted and inappropriate.  Of more relevance to the topic of this discussion, his (Mr Hammond’s) argument, attempting to prop up his earlier call for a moratorium on all gene drive research, is also poor.  Mr Adelman correctly notes that there is a framework in place to regulate laboratory use of infectious agents known to be able cause significant harm to human health, agriculture or the environment, if released into at least some types of receiving environment.  Though Mr Hammond counters that this relates only or primarily to human (e.g. worker) exposure, that is not the case - frameworks for livestock and plant pathogens, endemic and exotic plant pests, etc, are all well established.  Furthermore, many of these are known to be able to cause significant, widespread effects from a very small release, as Mr Hammond speculates might be the case for an organism carrying a gene drive system.  Furthermore, being capable of efficient horizontal transmission, most such infectious agents can spread far more rapidly than any gene drive system (which is restricted to vertical transmission; for the systems with which I am familiar that essentially restricts them to a maximum rate of increase of 2x per host generation).

I completely support Mr Adelman’s comment that “Whether to work with a specific pathogen, and under what conditions, is a decision made by biosafety authorities and governmental agencies on a case-by-case basis. I have yet to see a proper rationale stated in these discussions as to why gene drive technology (which is may be as diverse as the types of pathogens we work on), would require a different framework.”  While Mr Hammond notes that some countries prohibit some narrow types of activity (he suggests “experiments conferring bacterial resistance to clinically relevant antibiotics” and “gain-of-function experiments with certain pathogens”), this strengthens rather than counters Mr Adelman’s argument - at least where I am familiar with the examples, those decisions were taken on exactly the case-by-case basis that Mr Adelman outlined.  It may be that some very specific gene drive system/host species combination, or other synbio product, may be considered too hazardous for use in available laboratories in a particular location - with the current state of play it is not obvious to me what those would be, but this is a fast-moving field - but that fits well within the framework outlined by Mr Adelman.

Dear members

I request kindly not to use others names. Please don't take things personally also. It’s a scientific discussion and should only be treated as a discussion in arriving at a conclusion.

thanks a lot

This dangerously verges on a tit-for-tat that would not be constructive but since a prior post misstates so many things, I feel obligated to reply.

At no point in this forum have I called for a moratorium on all gene drive research.

I did not state that present biosafety systems exist "only or primarily to human (e.g. worker) exposure" (although it certainly is a prime consideration!)

You mischaracterize the point with respect to a small release and the differentiation I draw from the pathogen example.  If one takes B. anthracis as an example, the primary concerns in the event of a "small" release are livestock and humans, and not the establishment of populations of laboratory-modified anthrax in the place of existing ones, as the means to control anthrax outbreaks are well-known and, generally, there are not relevant populations of B. anthracis in the environs outside labs to be replaced with the lab model.

The case of gene drive mosquito, however, may be markedly different on both of those latter counts.  The "vertical transmission" assertion is irrelevant if the methods and means to identify and eradicate lab escapees does not exist. Indeed it is well worth noting that a feature of some gene drives - being inherently uncontrollable upon release - is precisely why P4 (BSL-4) labs exist. 

The US moratorium on funding of gain-of-function experiments, some of which involve synthetic biology, was not implemented on a case by case basis and does in fact function as a prohibition on a class of experiments.  When it was implemented, a number of ongoing projects were halted, those being experiments that deliberately or likely could result in a select group of organisms acquiring deleterious characteristics not found in nature.  (There are other examples of specific prohibitions that could be discussed.)

You correctly echo Mr. Adelman that "there is a framework in place to regulate laboratory use of infectious agents known to be able cause significant harm to human health, agriculture or the environment, if released into at least some types of receiving environment."  Unfortunately, not enough thought has gone into ensuring that this framework is adequate to the task of ensuring safety with synthetic biology, certainly gene drives being Exhibit A of this problem right now.

My point actually echoes one you and others adamantly made earlier when I called some gene drives "pathogen-like".  Some people protested this characterization, noting that gene drives are distinguishable from pathogens.  I agree with that point, they can be "like" pathogens but not are not the same. 

As you note, our framework for lab biosafety with particularly dangerous or high-impact self-perpetuating organisms (if released) has largely been drawn up with pathogens in mind.  But gene drives are not pathogens, as you too proclaim, so there is work to be done.  If I have built a container for a dog, that does not mean that it necessarily works for a mouse.

Greetings Mr Hammond,
Accidents and incidents happens more often than we think most of them accidental but also some have institutional and individual responsibilities and also we can face an intentional one.  In the spirit to contribute to this interesting exchange of opinions, sometimes fascinating for me, I would like to draw the attentions on the issue of Biosafety and containment to understand better what we are facing.
Regarding the scope of terms and definitions and the practice of the state of the art, could be useful in understanding mainly the topic of containment and the Biosafety Levels where for instance, a research take place.

First of all, I would like to pointed out that the term Biosafety and its scope is not the same in the context of The Cartagena Protocol and as use for traditional biosafety, for instance medical or veterinary labs, although very related, also the risk assessment and management are a little bit different. It’s a very specialized issue for professionals in biosafety indeed.

Cartagena Protocol on Biosafety

Introduction

“Biosafety is one of the issues addressed by the Convention. This concept refers to the need to protect human health and the environment from the possible adverse effects of the products of modern biotechnology”

Definitions
(b) “Contained use” means any operation, undertaken within a facility, installation or other physical structure, which involves living modified organisms that are controlled by specific measures that effectively limit their contact with, and their impact on, the external environment;

General principles

3. "Risk assessment should be carried out in a scientifically sound and transparent manner, and can take into account expert advice of, and guidelines developed by, relevant international organizations."

Canadian Biosafety Standard, Second Edition, 2015
is available on the Internet at the following address:
http://canadianbiosafetystandards.collaboration.gc.ca/

Biosafety
“Containment principles, technologies, and practices that are implemented to prevent unintentional exposure to infectious material and toxins, or their accidental release.”

Note 1: As the result of this combination of principles of biosafety we have different biosafety levels BSL-1 to 4

“The Canadian Biosafety Standard (CBS) describes, according to containment level, the physical containment requirements, operational practice requirements, and for facilities where pathogens, toxins, or other regulated infectious material are handled or stored. In the context of the CBS, “handling or storing” pathogens or toxins includes possessing, handling, using, producing, storing, permitting access to, transferring, importing, exporting, releasing, disposing of, or abandoning such material.”

Note 2: The term pathogen in this Standard is used in a wide manner:
2.3.1 Pathogens and Risk Groups
“A pathogen is a microorganism, nucleic acid, or protein capable of causing disease in humans or terrestrial animals. This can include bacteria, viruses, fungi, parasites, prions, recombinant DNA, genetically modified microorganisms, viral vectors, and synthetic biology products.”

Infectious material
“Any isolate of a pathogen or any biological material that contains human or animal pathogens and, therefore, poses a risk to human or animal health.”

On the other hand, the NIH Design Requirements Manual Revised on April 2017
In page 412 stated that:

“Special Applications including but not limited to Good Large Scale practice (GLSP). Recombinant DNA (As defined in the NIH Guidelines for Research Involving Recombinant or Synthetic Nuclei Acids Molecules, and work with specials vectors (such as arthropods) or certain select agents and pathogens of veterinary significance which may be subject to additional requirements that are to be addressed on a project-specific basis….”

Additional and more specific information regarding this post:

• NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (April 2016) http://www.osp.od.nih.gov/
• Laboratory biorisk management standard CWA 15793:2008 (E)
• Laboratory biorisk management CWA 16393 January 2012
Guidelines for the implementation of CWA 15793:2008
• Risk management ― Risk assessment techniques ISO/IEC 31010: 2015`
• International Federation of Biosafety Associations
IFBA Launches 3 new Professional Certifications - Biosecurity, Biocontainment Facilities and Biosafety Cabinets

Kind regards,
Dr Lázaro Regalado

To the question posed that about potential impacts I would like to provide a peer-reviewed paper by myself and an international group of conservation-minded authors about the potential benefits and risks of synthetic biology as applied to some of our most intractable biodiversity challenges.

http://www.cell.com/trends/ecology-evolution/abstract/S0169-5347(16)30197-5

As we are all aware there are many threats to biodiversity for which we do not have solutions or solutions do not affect rapid enough change. In a world completely altered by humanity it is likely that only a human generated solution can change the course of some of these challenges. Perhaps with appropriate rigorous testing, risk assessment and robust public discussion synthetic biology my provide solutions to some of these challenges. Not all will be appropriate as they might cause further problems in the environment but it is just as likely that the right solution in the right time and place may make a difference that none of our other tools can make. Thank you kindly for your consideration of my thoughts on this topic.

My thanks to Antoinette Piaggio [#8549] and to Kent Redford [#8489] for providing examples of potential applications of synthetic biology that may be beneficial for biodiversity.  And as Antoinette cautions, actual use will require rigorous testing, risk assessment, and public discussion.

Unfortunately, the link to the publication Antoinette mentions is broken.  An open access link to that paper is here:
http://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=2884&context=icwdm_usdanwrc

Regards to all,
Robert Friedman

As of  this posting (le Jour de la Bastille 2017), the following messages refer favorably to a case-by-case approach to the risks and benefits of synthetic biology: Topic 1- [#8409], [#8410], [8417], [#8418] [8427], [#8430], [8435], [#8447], [#8448], [#8466], [#8486],  [#8528], [#8536], [#8541], [#8553]; Opening Discussion- [#8437], [#8439], [#8441], [#8446], [#8453], [#8454], [#8546]; Joaquim Machado- [#8482].

Somewhat critical is Elpidio Peria [#8473]: “what we may need to eventually consider is whether the case by case approach of Cartagena may still be a sufficient approach for dealing with these latest developments”. More critical than Mr. Peria is the posting of Edward Hammond [#8543].

The conflicting opinions about the cases are reason for abstraction. How would economists evaluate the risks v. the expected benefits of any particular case? Three alternatives exist: (1) stringent regulation, (2) the free market or (3) a regulated market. Choosing the first alternative assumes that the bureaucracy is sufficiently equipped and nimble to rule on a flurry of diverse applications. Choosing the second assumes that industry is sufficiently capitalized to cover the liability of a worst-case scenario. Because both assumptions are universally and obviously false, the regulated market should be examined, which would fall under Article 27 of the Cartagena Protocol “Liability and Redress” and subsequent COP-MOP Decisions and Documents on Liability and Redress (http://www.gmo.hr/eng/Cartagena-Protocol/Liability-and-Redress/COP-MOP-Decisions-and-Documents-on-Liability-and-Redress )

Many comments suggest that the risks are exaggerated and reflect speculation or hyperbole (e.g., [#8410] or [#8437], [#8453]). Should insurers likewise overestimate the hazards, handsome profits in the insurance market will invite competition and lower premiums. The regulated market (Alternative 3) would satisfy the recommendation of a case-by-case approach and the aforementioned critical comments. Mandatory insurance without a limit on indemnification is essential for the risk not to exceed the expected benefit. Under such a framework, an uninsurable endeavor could not be legally pursued.

For highly capitalized biotechnology, the premiums paid will be less costly than waiting for the bureaucratic evaluation of an application and appealing any denial (Alternative 1). However, another factor enters the analysis: many firms in the industry are undercapitalized, especially the start-ups. They may perceive that shallow assets are a competitive advantage for endeavors that entail significant risks. Should the worst-case scenario eventuate, they could displace the costs to the public through bankruptcy. Although many entrepreneurs may reason thus, most will recognize that the free market (Alternative 2) is a political impossibility.  For judgement-proof firms, ironically, Alternative 1 (stringent regulation) is preferable to Alternative 3 (regulated market) because time is bought as the regulatory apparatus is painstakingly negotiated.

To fully comprehend the subtleties involved in a regulated market with mandatory insurance (Alternative 3), one must delve into the microeconomic sub-field “information, knowledge and uncertainty” (Journal of Economics Literature Code D8 “Information, Knowledge, and Uncertainty”).  How can the COP engage the relevant economics while  insisting  that “genetic resources” be “material” and not “information”? The conundrum of sticking to the fundamentally flawed AHTEG definition persists.

Re: Post #8509  -  I am not familiar with the journal articles quoted regarding off-target effects of CRISPR by    (Nat Biotech 33, 822; Nature Biotech 33, 1679; Nat Methods 12, 237). I tried to track them down without success and would be grateful if she could give author names and/or titles. Much is made of the analysis of off-target effect of CRISPR in these articles and I would like to take a closer look.
It is possible that the study intended was  Fu et al, Nat Biotech 2013, vol 31, pp822 article which uses overexpression of Cas9 and sgRNAs, which was conducted in human cells with overexpression plasmids for Cas9 and sgRNA and a process of deliberate mismatching to reduce on target effects. The conclusions were to refine the on target function if these tools are to be used in human medicine.
It is therefore important to remember that when interpreting the data and conclusions how and why a study was conducted, also the context - in this case human medicine, not agriculture and the environment. Finally it is pertinent to consider that a study conducted 4 years ago in this field will rapidly fall behind current developments.
The mouse study Schaefer, et al. Nature Methods 2017 also has to be understood in relation to the use of 2 mice and 1 guide combined with use of plasmid DNA injection along with Cas9 protein, which most regard as "overkill" to push the nuclease activity. This would not be a method used in agricultural applications, not in a gene drive.
This would be like trying to sculpt the hands of the Venus de Milo with a sledgehammer - a undesired outcome would be highly likely. 
We should take caution in leaping to conclusions about the problems with CRISPR and understanding that with new technology developments and improvements (in function and safety) steadily follow. Just think of the cars and phone your parent drove and spoke into.

Just to say that I fully support the view posted by Ms. Jeshima k Yasin, India [#8542]
Respectfully

Dear all--

Though I am sure that this topic will be discussed further during the following two weeks of this online forum, I would like to add my perspective to the conversation about contained research on gene drives in postings #8532, #8535, #8536, #8538, #8541, and #8543.

In #8543 Ed Hammond offers the opinion that “Unfortunately, not enough thought has gone into ensuring that this framework is adequate to the task of ensuring [laboratory] safety with synthetic biology, certainly gene drives being Exhibit A of this problem right now.”

I disagree.  Much thought has been given to biosafety of synthetic biology in general, and gene drives as a specific example.  Other participants presented ongoing discussions of guidance for contained gene drive research in the Netherlands (#8439), Germany (#8533), and France (#8546).  In an earlier posting (#8435), I referred to consideration by the World Health Organization’s Vector Control Advisory Group.  Many have referenced the US National Academies of Sciences, Engineering, and Medicine, “Gene Drives on the Horizon”.  Researchers, funders of research, and the regulatory community have all been attentive to biosafety concerns.

I would like to make sure that one additional point is clear.  Ed Hammond refers to a moratorium on “gain of function” research in the US as an example of a prohibition on class of experiments.  While such a moratorium did exist, it was rescinded in January 2017.  Currently, review of such research proposals are done on a case-by-case basis.  (A position advocated for both gene drive research and review of synthetic biology, in general, by many in this forum.) 

My thanks to everyone for a lively and informative first session.

Regards,
Bob Friedman

POSTED ON BEHALF OF Irla Élida Vargas Del Ángel (Note: this message arrived at the Secretariat before the closing of the discussion.)
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As an Indigenous woman, I do not have a concept for Synthetic Biology because we do everything naturally. However, from the readings I see that the interaction and modification of leaving organisms may cause alteration on the environment.
One of the fundamental rights is the right to food which is the basis for our life. If the natural seeds are contaminated, they will be modified and displaced, in short time we will lose our pure and natural seeds.
Indigenous Peoples have been the guardians of the natural seeds which were and still are the core for our survival. For Indigenous women, the variety of food is for physical and spiritual nourishment within a close link with Mother Earth. The food is also an act of love that includes the culture, our feelings, and our relations.
We do not know the impact of the seeds alteration on human being’s health, on other living beings, such as the ants and worms in the chain of food and in the local production of Indigenous Peoples.
Irla Élida Vargas Del Ángel
Nahua Indigenous woman from México

POSTED ON BEHALF OF Yolanda Teran (Note: this message arrived at the Secretariat before the closing of the discussion.)
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My name is Yolanda Teran, an Indigenous woman from the Kichwa nation from Ecuador. I am the Coordinator of Education of the Indigenous Women Network on Biodiversity from Latin America and the Caribbean.
Synthetic Biology is a controversial issue that still is on experimentation and the consequences on living things, on humanity and on Pachamama, Mother Earth are still unknown. Within our Indigenous epistemologies every plant, animal, river, stone, mountain, star….has a geographical space and  ecosystems which resilience depends on the quality and strength of different types of relationships.
These relationships are carried out within the Indigenous calendar and the Cycles of Life and Agriculture. These cycles are full of ceremonies, chants, offerings, these are activities based on cultural identity, languages, ancestral mandates, principles and values such as solidarity, reciprocity, care one another, care, love and protect Mother Earth, natural laws, costumary law, ancestral systems of governance and so on.
Indigenous women are the keepers of the culture, language and seeds which are sacred beings for us because thanks to the variety of them we also have a variety of produce for the humanity survival. Since early childhood we learn to do things for our daily life in natural way respecting the Mother Earth and the life of human beings. We believe that if a small thing is moved or changed from an ecosystem there will be immediately lack of balance and harmony in human life and in the relationships. 
Yolanda Teran