Dear Forum members,

I have helped to develop the section on LM Mosquitoes of the Guidance as coordinator of the sub-working group and I would like to ask for your contribution to the improvement  of this topic, initiating a discussion on issues appointed during the review process as in need for further improvement. I would kindly ask you to refer to the original submissions made by the Parties available at:
http://bch.cbd.int/onlineconferences/guidance_ra/review.shtml#download,

and to summary of the recommendations prepared by the Secretariat, available at:
http://bch.cbd.int/onlineconferences/guidance_ra/review.shtml#comments. 

Please note that more than half of the respondent Parties noted that this section of the Guidance lacks relevant issues that should have been included. It will be very useful to us that these issues are pointed out.

Some Parties also recommended the addition of practical examples of risk assessment of LM Mosquitoes. Can you indicate any source where risk assessment reports or files are available?

During the preparation of this section of the Guidance we received many suggestions of background documents that should be used together with the Guidance. It is a long list and I would like to ask your help by appointing  those documents and other tools that are of greatest relevance to be used together with the guidance, so that we can improve the current list.

Thank you and best regards,
Eliana

Dear Colleagues,
Among the recommendations of the reviews of the LMO mosquito section was to include paratrangenesis. This is a method by which a bacterium or virus that is associated with the insect is modified by modern biotechnology in order to create a novel phenotype in the insect. There are two kinds of microorganisms being investigated for doing this in mosquitoes and other insects. (1) The microorganism may have a specific, symbiotic relationship with the insect, or (2) it may be commonly associated with the insect but does not have an obligate relationship.

The expected application is to release these microorganisms with the expectation that the mosquito would become infected or consume them and maintain them in their gut.

My question to you, is if transgenic mosquitoes are not being released but rather wild populations are the target which is expected to become infected, should this be considered under the heading of LMO mosquitoes in the context of this document ? Or should such applications be considered as LMO biopesticides whose target is mosquitoes, which it seems to me, would place them outside of this document?

Thanks,
Mark Q. Benedict

Dear Eliana

In response to your request for publically available documents on risk assessment of GM mosquitoes,recently several countries have made decisions on open release of self-limiting Aedes aegypti mosquitoes.  Only one of these is currently in the BCH (Malaysia) and I attach the link to this.  Brazil and Cayman have also taken decisions on open releases and I attach the Brazilian decision ( in Portuguese). A risk assessment document was prepared for Cayman based on Annex III of the Cartagena Protocol, with elements from the Pest Risk Analysis of the IPPC, as the relevant international legislative framework.  The Cayman risk assessment is available from the UK Libraries of the House, as notification was required to the UK authorities under EU Regulation 1946/2003 on the transboundary movement of genetically modified organisms.
Other risk assessments I believe are in preparation as other countries around the world consider decisions on the open release of GM mosquitoes.

Additionally I provide two published papers on the risk assessment of genetically modified Aedes aegypti mosquitoes, and one report on the  risk assessment of Aedes aegypti, that are infected with Wolbachia.  This is not an LMO, but has similar features from which to draw advice for risk assessments. I believe this is already in the BCH.

these documents should of assistance in the refinement of the LMO mosquito risk assessment guidance.

Published papers

Beech et al 2009 http://www.msmbb.org.my/apjmbb/html173/173cont.htm
Patil et al 2010 http://www.msmbb.org.my/apjmbb/html182/182cont.htm
Murphy et al 2010  http://www.eliminatedengue.com/Portals/58/PDFs/NEW-Risk%20Analysis%20of%20proposed%20Wolbachia%20Aedes%20aegypti%20release%20Final%20Report%20for%20public%20release%209%20March%202010.pdf

Cayman Islands risk assessment for genetically modified mosquitoes
http://www.parliament.uk/deposits/depositedpapers/2011/DEP2011-0053.pdf

Malaysian government opinion on open release of GM mosquitoes: : http://bch.cbd.int/database/record-v4.shtml?documentid=101480
Brazilian government opinion on open release of GM mosquitoes: see attached document


Camilla Beech

Dear Colleagues,

As regards the guidance on LM mosquitoes, I would like to bring particularly to your attention one of the comments submitted by the Belgian Biosafety Advisory Council, i.e.

"The development of LM mosquitoes, in particular in the frame of a self-propagating strategy, raises specific questions as regards their risk assessment and also the application of the provisions of the Cartagena Protocol. Indeed, it should be underlined that mosquitoes, being LM or not, have very broad dissemination spectra and that it will be very unlikely (if not impossible) to deal with their containment in the importing country only. Releasing LM mosquitoes will therefore intentionally or unintentionally affect several countries. This should be taken into account in the frame of the risk assessment. This should also trigger a broader reflexion on how the Protocol should apply to this type of LMOs, taking also into account the provisions of Article 17 on Unintentional Transboundary Movements, and Article 25 on Illegal Transboundary Movements."

Best regards,

Dear participants,

Related to the guidance on "Living modified mosquitoes" and more particularly to the question of Dr. Mark Benedict, I would also like to point out following remark that has been raised in the frame of the Advice of the Belgian Biosafety Advisory Council :
“Although the focus of the guidance is on LM mosquitoes, it is mentioned that the guidance may be useful for the risk assessment of similar non-LM mosquito strategies. Within this respect, paratransgenesis could be mentioned in the introduction as an alternative approach to introduce effector genes into mosquitoes by utilizing genetically modified insect symbionts to express molecules within the vector that are deleterious to pathogens they transmit. Another reason to mention this approach is that paratransgenesis can be used in both population suppression strategies and population replacement strategies.”

Since paratrangenesis uses modern biotechnology techniques with the aim of developing mosquito strategies, it could be considered within the guidance of LM mosquitoes. 

Kind regards,

Dear forum participants,

Thanks to my Belgian colleagues to start to intervene in the discussion.


In the frame of the advice of our Belgian Biosafety Advisory Council, it
was also pointed, relatively to the guidance on LM mosquitoes, that the
guidance should more explicitly be elaborated more distinctly for LM
mosquitoes intended for population suppression strategy on one side and
for strategy of permanent replacement on another side; the latter being
aimed at replacing wild mosquito populations by LM mosquitoes could need
more constraining risk assessment than the former relying on
self-limiting systems.

In addition, it was also pointed that, taking into account the extremely
various strains of mosquitoes around the world ( with different
behaviours, ecological niches, capacity of pathogen transfer, ... ) , a
very complete characterisation of the strain used, including the use of
reliable molecular markers and precise biogeographic origin, would be a
first essential requirement.

With best tegards.

Lucette Flandroy



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Dear forum members,

I would like to agree with the last posting by Lucette regarding splitting the guidance, depending on the strategy, as they have very different risk assessment profiles.
Guidance on LM mosquitoes should be elaborated separately for population suppression or self-limiting strategies on one side and
for population replacement or self sustaining strategy on another side. Paratransgensis could be a third category. Self sustaining LM mosquitoes represent a strategy that may require regional or even international approaches to risk assessment as identified in the forum, whereas self-limiting approaches have a more local application  and national decisions could and have already been made regarding this approach.

I disagree somewhat with the suggested requirement for the  " the use of
reliable molecular markers and precise biogeographic origin"  as this just tells you the identity of the mosquito and does not relate to a risk profile or indeed any of the parameters mentioned ( ecological niche,behaviour, pathogen competence of the mosquito). Additionally it is very unlikely that the precise biogeographic origin could be determined. At best, strains of mosquito, used for transformation could come from pooled field collections and the country and region might be known but not a precise reference.

regards
Camilla Beech

Dear Colleagues,
If you are interested in the subject of Cartagena and its adequacy to address self-propagating transgenic mosquito strategies, you may wish to see:

Ostera and Gostein
http://jama.ama-assn.org/search?fulltext=ostera+gostein&submit=yes&x=0&y=0

and

Marshall
http://www.nature.com/nbt/journal/v28/n9/full/nbt0910-896.html

Both of these articles discuss the Cartagena Protocol's capacity to address the novel issues raised by this technology.

Mark Q. Benedict

POSTED ON BAHELF OF LETICIA PASTOR CHIRINO

-----

2nd Message to post in the LM Mosquitoes section.

Genetically Modified Mosquitoes.

a. The risk assessment of the Genetically Modified Mosquitoes can be undertaken following the steps and principles set on the Road Map.

b. I believe that huge gaps in the current knowledge on this particular subject still remain, which in terms of risk assessment, is considered as uncertainty.

c. The treatment of the uncertainty, in this case, must be focused on the results of the scientific research and tests.

d. Taking into account the existing uncertainty on this matter and the possible impacts that the release of this kind of organisms could bring to other species, I consider that the work of this group must be kept for more time, so that a greater exchange of experiences can be undertaken and the next steps to follow be conducted upon more real and scientific bases.

e. Concerning risk management strategies, paragraphs b and c, it would be useful to introduce concrete examples on this mechanisms and methods. I consider that here, we are dealing with a problem that deserves a special attention, considering that one of the reasons for the application of this technology, is precisely, the low efficiency proved by  physical, chemical and mechanical methods applied for the control of these vectors to date.

Dear participants.
Transgenic mosquitoes are a novel strategy for the control of endemic diseases. An ever growing set of strategies to obtain these mosquitoes have been published or are presently in development. I think that the accumulated experience with transgenic mosquitoes which can be considered enough to concretely evaluate risks (both in controlled release and commercial approvals) is reduced to one single archetypal construction: that of OX513A bisex RIDL strain or similar ones. Even for other RIDL varieties, as the flightless female strain, the accumulated experience is scarce.
A general guidance for the RA of transgenic mosquitoes, as bravely attempted by the AHTEG, does not seem adequate: it is simply impossible to draw a realistic problem formulation for such a large set of species, constructions, possible receiving environments and objective and scale of the intended release. For instance, as recognized by the AHTEG, “The (transgenic) strategy used is an important factor to be considered in the risk assessment and risk management process since there might be different points to be considered, depending on the specific strategy used”. I strongly suggest AHTEG should withdraw the text or concentrate on a guidance for male-sterile RIDL mosquitoes only, just as an exercise of the roadmap use.
To support my point of view I will briefly comment some issues raised by the AHTEG in the mosquito guidance text.
a) “In many of these environments few studies have been conducted to examine gene flow among vectors, their mating behaviour, the interactions between vectors sharing one habitat, how pathogens respond to the introduction of new vectors, etc. Such information may be needed to establish a baseline in order to successfully assess the risks of LM mosquitoes”. What is meant by gene flow among vectors? If the same species is meant, than a large amount of hard data is available for all important vector species, including cullicids, triatomines, phlebotomines, etc. If gene flow among different species is meant, I would assume that this flow would happen by mating: insects are exquisitely equipped for that and the occurrence of inter-specific gene flow is very rare, if not plainly absent. Is this issue really relevant? Moreover, for the RIDL technology, this is irrelevant at all. On the other hand, mating behavior is also well know for most vectors and as far as I know there is not a suitable body of evidence to support the existence of local differences that could represent an important issue for the release of GM mosquitoes, except for its success or failure. This is, however, not a safety issue, but an economic one. The third issue refers to a possible interaction between vectors. This may be relevant in wild habitats, although I sincerely was unable to find any reference on that. Just on the opposite: the coexistence of many vectors, even for the same disease and for the same hosts is the rule…(e.g., triatomines). Finally, I would like to come to the last issue: How pathogens respond to the introduction of new vectors. As far as I understood from previous published trials and from the general strategy of vector control, the idea was always to introduce a GM variant of a local vector. What was really meant by a new vector? Are the authors of the text supporting the idea that a GM A. aegypti is a new vector?

b) “New or more vigorous pests, especially those that have adverse effects on human health: (i) the released LM mosquitoes may not function as expected, for example gene silencing or production failures could result in the release of non-sterile or competent mosquitoes and thus increase the vector population or disease transmission; (ii) the released LM mosquitoes could transmit another disease more efficiently than indigenous non-LM mosquitoes, such diseases might include yellow fever, chikungunya, etc.; (iii) suppression of the target mosquito might result in the population of another vector species to increase and result in higher levels of the target disease or the development of a new disease in humans and/or animals. These other vector species may include other mosquito vectors of other diseases; (iv) the released LM mosquitoes might become pests; (v) the released LM mosquitoes might cause other pests to become more serious, including agricultural pests and other pests that affect human activities”. The first issue (sub-item 1) is not to be expected, as no one would use such a fragile technology for the control of any insect transmitted human disease. Even if it happens, it will be readily identified in the field trials. Nothing similar can happen in a commercial release, obviously, but even if it were the case post-release monitoring would indicate the problem. The risk management of such technical failure is very simple in RIDL mosquitoes. As for other technologies, it could be more difficult, but sound, clear examples (supported by literature) instead of theoretical hypotheses would help the reader to come up with plausible solutions. As for item ii, we should keep in mind that if the strategy is not population replacement, but population reduction (as for RIDL transgenic mosquitoes), it is not a worry at al. Vector capacity of different sub-species or varieties do vary, but as far as I now never with such an intensity as to significantly change the epidemiological scenario. Again, the literature should support this hypothesis, but I could not extract from all papers cited in the references sub-page what were those supporting this idea. Sub-item III seems more logical: a vacant ecological niche will be occupied by other species. But why by other vectors? There are thousands of species competing for the vacant niche of an eradicated A. aegypti, for example, but even Culex or Anopheles could not readily occupy this vacancy. This, again, sounds too speculative and makes the problem identification an impressive, but ill defined subject. Sub-item V is also too speculative: what are the vectors of human diseases that could play such a broad role as to “cause other pests to become more serious, including agricultural pests and other pests that affect human activities”? I simply cannot imagine how a transgenic mosquito would change its behavior in such an extent as to endanger other, new vertebrate species. Is there any example in the literature?

In conclusion, from the critical analysis of just a small fragment of the text, many more questions are raised than true guidance. Indeed, questioning is the way to knowledge, but I doubt if this was the methodology adopted in this guidance text.

As a final remark, I would like to reinforce the need to stick to the regular way of citing the relevant literature, i..e., immediately after each statement and not in a collective form in a web-linked sub-page. This is true for the other practical texts in Part II and is very inappropriate for a sound, scientific, critical reading of the text. I hope my criticism will be understood as a sincere effort to improve the RA guidance text.

Thank you and best regards.
Paulo Andrade/ Dept. Genetics-UFPE/ Brazil

Dear forum participants,

First of all, thenks a lot to Paulo Paes de Andrade for his long and
interesting messsages .

I would like to make some general remarks on these comments.

Concerning your comments on Stacked genes, Mr. de Andrade:
I Think that severel of your statements could indeed be right providing:

1) present available knowledge and methods could detect all potential
intended and unintended changes a) in the structure and in the function
of the genome and b) in all other molecules and their function deriving
directly or indirectly from the genome functionning and c) in their
interactions.
2) the regulators require that all these potential changes are looked
at.
If the real situation was so, then indeed all potential changes in the
"single genes" would be detected and the RA for



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Dear Lucette.

Thanks for your remarks. Stack risk analysis is really a challenge and I would like to further comment on that, taking into account your remarks, but the post was truncated. Could you complete it for all forum participants, please?

Kindly,
Paulo Andrade
Dept. Genetics/ Fed. University Pernambuco
and
CTNBio (Brazilian Authority for GMO)

> Dear forum participants,
>
> First of all, thanks a lot to Paulo Paes de Andrade for his long and
> interesting messsages .
>
> I would like to make some general remarks on these comments.
>
> Concerning your comments on Stacked genes, Mr. de Andrade:
> I Think that several of your statements could indeed be right
> providing:
> 1) present available knowledge and methods could detect all potential
> intended and unintended changes a) in the structure and in the
> function of the genome and b) in all other molecules and their
> function deriving directly or indirectly from the genome functionning
> and c) in their interactions.
> 2) the regulators require that all these potential changes are looked
> at.
> If the real situation was so, then indeed all potential changes in the
> "single genes" would be detected and the RA for stacked genes could
> indeed be somehow simplified.
>
Besides, part of the RA of stacked genes of LMOs is somehow different
than for conventional crossings between non-LMOs precisely in order to
inquire in the stability of the concerned genetic regions in that
specific situation and to look if it would precisely not be somewaht
different than in crossings between non-transgenic varieties.

Concerning some of your interesting statements relative to LM
mosquitoes: whereas it is indeed useful to argue some problem
formulation by reporting analogous already occured problems, I thnk that
the litterature cannot necessarily give examples to support each and all
of the plausible risk hypothesis made, since we are confronted with new
situations.

With best regards.

Lucette Flandroy


P.S. : I big your pardon for the fact that the beginning of this message
was sent unfinished by mistake
I could be without internet connexion for some days





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