Mosquito Larvae

EFSA gene drive working group fails independence test

Gene drive, a very controversial application of new gene editing techniques, is undergoing regulatory evaluation by the European Food Safety Authority (EFSA). But as half the experts tasked to assess the technology’s potential risks have financial links with organisations developing the technology, and others also have conflicts of interest with a company developing GM insects, EFSA's scientific opinion is going to be undermined before even being published. Time for the EU Parliament to increase the pressure on the agency to tighten its independence policy.

 

Obvious and serious conflicts of interest are still not in the past for the European Food Safety Authority (EFSA): a look at the agency’s working group on the risks associated to gene drive organisms makes this quite clear. For instance, two of the appointed experts are receiving funding from the Bill & Melinda Gates Foundation, which in turn funds research and lobby work in favour of the technology. Even according to EFSA’s own, rather weak, independence policy, one of these appointments should not have been made due to obvious conflicts of interest.

So why did EFSA put together such a problematic expert panel on an issue that is this sensitive? The agency has defended its choices, stating that the appointments are compliant with its independence rules – a claim which in one case is not correct in our assessment. Apart from showing that EFSA has not properly implemented its own rules in this case, the fact that several other grave conflicts of interest did not even trigger the policy demonstrates that there are still severe loopholes.

In 2017, the European Parliament requested that EFSA puts in place a "two-year cooling-off period for all material interests related to the companies whose products are assessed by the Authority and to any organisations funded by them". This simple approach would have prevented such a panel to be appointed, but EFSA preferred to keep loopholes in its 2018 independence policy revision.

After so many years of EFSA’s poor implementation and partial disregard of repeated EU Parliament requests to fix its independence policy, the new Parliament would be wise to step up the pressure on this EU agency.

 

EFSA created its working group on gene drive following the mandate it received from the European Commission in June 2018. This mandate requested EFSA to “identify potential risks in terms of impact on human and animal health and the environment that gene drive modified organisms could pose”; to “identify potential novel hazards of gene drive modified organisms”; and to “determine whether the existing guidelines for risk assessment are adequate and sufficient for gene drive modified organisms”.

EFSA accepted the mandate in August 2018, created the working group at the end of the year, and promised to deliver its opinion before March 2020. The agency organised a workshop to discuss the issues with various stakeholders in May 2019.

Gene drive is a new, potentially very risky genetic engineering approach through which scientists force a gene – thanks to genome editing techniques such as Crispr-Cas9 – into the population of a given species so that a desired trait is inherited at a higher rate and with greater certainty than through natural reproduction alone. If ever effective and released into the environment, this could enable the genetic re-engineering of an entire species in the wild, whether it be to eradicate or transform it - with vast implications.

So far, the technology has not proven to be reversible or containable, meaning mistakes must be avoided at all costs. As a result, the main current sources of funding for developing the technology are either philanthropy (the Bill & Melinda Gates Foundation) or the military (the US Department of Defense’s DARPA agency). As gene drive organisms can have military uses as well – US Director of National Intelligence James Clapper even listed genome editing as a potential weapon of mass destruction in February 2016 – the military is also seeking antidotes to it. In December 2017, CEO together with other groups documented how the Bill & Melinda Gates Foundation was funding lobby work at the UN Convention on Biological Diversity, in coordination with other US and EU lobby groups from the biotech and pesticides industries, to convince regulators worldwide to oppose a moratorium on the technology.

The development of gene drives has already led to major public controversy as well as debates among scientists, politicians and civil society. In November 2016, 170 groups (including CEO) called upon the UN’s Convention on Biological Diversity to place a moratorium on the technology. Scientists are calling upon all researchers working with gene drives to adopt the same security measures as those required for work with self-propagating pathogens like viruses.

For now, gene drives organisms have not been used in the wild, only in the lab. However, some companies are already developing GM insects for a comparable purpose of pests suppression, such as the British firm Oxitec (short for ‘Oxford Insects Technologies’), created in 2002 as a spin-off from the University of Oxford. The company was bought in 2015 for $160 million by the US synthetic biology company Intrexon (whose largest shareholder with more than 40% is Third Security, a US venture capital firm mostly investing in life sciences start-ups), which wants to “design and engineer living systems to address the world’s greatest challenges in health, energy, food, and environmental sustainability”.

Oxitec has released millions of GM Aedes aegypti mosquitoes in trials in Malaysia, Grand Cayman, Brazil and Panama. Aedes aegypti mosquitoes can carry multiple diseases, such as dengue fever and the chikungunya and zika viruses. Oxitec's mosquitoes have been genetically engineered so that their offspring dies before reproducing, thereby reducing the size of the disease-carrying population. A new version of Oxitec’s GM mosquitoes – called Friendly – includes a genome modification that causes all female offspring to die (only females feed on humans) but lets all male offspring survivors inherit the genome modification and cause their own female offspring to die, and so on and so forth. The gene is called "self-limiting" because, unlike a gene drive, it is supposed to eventually disappear from the mosquito population a few generations after the release.

Oxitec is also developing a GM version of Anopheles, the mosquito that carries malaria, with the help of $7 million in funding from the Bill & Melinda Gates Foundation.

But, beyond the charitable projects, Oxitec is also looking at much bigger markets, where the same technology could be applied to developing GM versions of the most common agricultural insect pests (including the diamondback moth, the fall armyworm, and the soybean looper moth).

While Oxitec claims positive results, these experiments are very contested : citizens of Florida have successfully blocked planned local experiments, and Grand Cayman’s government discontinued funding for the project due to “unsatisfactory results”. Indeed, the evidence that has become available on the releases undermines Oxitec's claims.

Meanwhile, the Bill & Melinda Gates Foundation’s Target Malaria project is releasing GM mosquitoes in Burkina Faso, but with the intention to pave the way for future releases involving GM mosquitoes carrying a gene drive.

Gene drive is a typical example of technology development that regulators have not yet come to grips with. EFSA’s opinion therefore comes in at a crucial moment, and the independence of the experts in its working group will be critical to deeming the resulting opinion trustworthy. However, an analysis of the Annual Declarations of Interest Sidenote (ADoI) of these experts shows that EFSA has failed to recruit a panel that will be reasonably independent, or that will even reflect the diversity of positions in the debate.

 

EFSA’s gene drive working group is dominated by experts with conflicts of interests

The working group includes six experts: Michael Bonsall (Oxford University), Andrea Crisanti (Imperial College London), Leslie George Firbank (Chair, University of Leeds), John Mumford (Imperial College London), Fabien Nogué (INRA, since June 2019) and Ernst Wimmer (Göttingen University).

A screening of the ADoI’s of these experts provides the following information (see annex for a detailed analysis). Among the six experts:

- Three (Bonsall, Crisanti and Mumford) have financial links with gene drive developers (Bill & Melinda Gates Foundation’s Target Malaria project, and the US DARPA).

- Two (Bonsall and Wimmer) have direct financial links with GM insects company Oxitec.

- One (Mumford) should not have been recruited by EFSA for the working group given the agency’s independence rules.

- All of the experts have financial interest in one or more commercial companies whose activity is in the remit of EFSA.

The appointment of these experts was enabled by current loopholes in EFSA’s independence policy (see box). These loopholes were allowed to remain in the 2018 revision of the agency’s independence rules despite repeated criticism by the European Parliament. In 2015, EFSA had already been criticised by the European Ombudsman on a very similar issue, GM insects and the details of the partnership between the University of Oxford and Oxitec - it appears from the declarations of interest that EFSA is now implementing this recommendation.

BOX- Independence of EU food safety experts: where are we today?

At CEO, we started scrutinising EFSA’s independence about ten years ago by reporting conflicts of interests among its external experts. Over the years there has been one scandal after the other.

At the same time, we’ve witnessed a very gradual improvement in EFSA’s independence policy. But this process is too slow. In 2017, when EFSA adopted its new independence policy, we found that two key loopholes had still not been closed:

  • The scope of the ADoI interests assessment remains too narrow; experts are only evaluated on whether or not their interests overlap with the specific mandate of the panel they’re applying to.
  • Private research funding for experts remains excluded from the two-year cooling-off period as long as the amounts in question do not rise above 25% of the annual research budget managed by the expert and/or his or her research team. With such a high ceiling, very few experts would not be appointed, all the more that funding coming from public-private partnerships is considered public funding...

The question of EFSA’s independence is particularly important to revisit today, as the EU just adopted a revision of its 2002 Food Law Regulation (which led to the creation of EFSA). This revision, which will enter into force from September 2019, will at last increase data transparency in the agency, potentially enabling meaningful scientific scrutiny on EFSA’s work and bridging the current gap between regulatory and academic science. In the package (provided Member States agree to it) is a hefty 75% budget increase for the agency. With these new additional resources, EFSA now has more means to organise its independence from the companies trying to obtain market approval for their products. Whether or not it will use these resources for this purpose remains an open question.

But there is at least one case in which the expert should not even have been recruited, according to EFSA’s own independence policy. John Mumford’s interests include his role as director of a local farming company in the US, and EFSA’s current independence rules exclude experts with “financial investments with business actors directly or indirectly impacted by EFSA’s operations ... The same holds true for current employment engagements.”

The same expert also declared receiving about 50% of his annual research budget from the Bill & Melinda Gates Foundation’s Target Malaria project on GM mosquitoes. But EFSA’s independence rules also exclude experts who receive more than 25% of their annual research funding from a source whose interests conflict with the mandate of the group they’re applying to.

All this begs important questions: given that the topic is so sensitive, why did EFSA do such a poor job in gathering an independent, or at least diverse, expert group? Why the dominance of experts with financial links to developers when the gene drive issue has gathered such a broad interest in the scientific community?

EFSA provided detailed answers to these questions, stating that in order to identify the members of the group "EFSA together with the chair of the WG agreed on the fields of expertise to cover [Arthropod genetics/genetic control strategies in insects (focusing on mosquitoes and agricultural pests as these are the most likely cases moving to practical applications), Molecular biology and Environmental risk assessment (ecological modelling, population genetics, non/target effects, risk assessment of invasive species)] and EFSA then performed literature searches to identify relevant experts based on the volume and relevance of identified scientific publications".

The agency explained that its current independence rules did not warrant the exclusion of any of these experts (but for example that Pr. Mumford could be a member but not a vice-chair or chair of the group given his patent), notably because it considers public-private partnerships as public funding (which is debatable to say the least). It looks like their assessment of Pr. Mumford's situation is incorrect however, as they explain that "the overall amount of private funding received for research activities conducted in the areas of concern is below the threshold of 25%" whereas Pr. Mumford himself states that his funding from the Bill & Melinda Gates Foundation "accounts for approximately 50% of the research funds managed by me".

Will EFSA keep the working group’s composition unchanged? And after so many years of EFSA’s poor and sometimes non-existent implementation of the European Parliament’s repeated requests to close the loopholes in its independence rules, wouldn’t it be time for the Parliament to step up the pressure a bit?

 

CORRECTION: an earlier version of the article mistakenly stated that "One of the leading companies in the gene drive field is the British firm Oxitec". Oxitec has not developed gene drives yet as far as we can tell but works on other (unproven) types of GM insect biocontrol biotech applications. The article has been revised accordingly.

 

Photo: Larve de moustique, Thomas Bresson (some rights reserved)

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ANNEX - Detailed listing of the problematic interests in the ADoIs of EFSA’s gene drive working group members

Michael Bonsall is Professor of Mathematical Biology at the University of Oxford, with managerial duties in St Peter’s College. An expert in mathematical modelling, Prof. Bonsall has been a key developer of GM insects in the UK for years. His declaration of interests, filed with EFSA in January 2019, features several financial links to gene drive developers:

  • Two PhD students in Prof. Bonsall’s group have been funded by the Biotechnology and Biological Sciences Research Council (BBSRC, a public body funding biotechnology research in the UK) in a joint grant between Oxitec and Oxford University.

  • Prof. Bonsall received a research grant from the US DARPA on the economics of mosquito control for the period between April 2016 and October 2017. The goal of this grant was to “evaluate the economic and ecological implications of transgenic mosquito control”.

Prof. Bonsall’s funding from the BBSRC on ‘Insect Resistance Management’ was a joint grant between Imperial College London, Oxitec and the University of Oxford.

Bonsall has also had a number of quasi-regulatory roles on the issue, as a science advisor to the 2015 House of Lords’ inquiry into GM insects, and as a member of the Gene Drive Working Group of the BBSRC (which distributes research funding in the UK).

Andrea Crisanti is a Professor of Molecular Parasitology and Microbiology at Imperial College London. His declaration of interest shows three relevant financial interests when it comes to gene drive technology:

  • A grant from the BBSRC running since 2007 entitled the “Analysis of the sex differentiation pathway in Anopheles mosquitoes”.

  • A grant from the Bill & Melinda Gates Foundation running since 2005 on “Assessing the suitability of the HEG for driving genetic modifications into mosquito population”.

  • A grant from DARPA to the Harvard Medical School at the Massachusetts General Hospital (with Imperial College as a subcontractor) on antidotes to gene drives: “Technologies to control, surveil and counter genome-editing nucleases and gene drives". This research is based on pre-empting possible military uses of the technology.

Leslie George Firbank is a Professor in Sustainable Agriculture at the University of Leeds. He’s also a member of EFSA’s GMO panel, and chairs the EFSA working group on gene drives. While his declaration of interest (filed at EFSA in mid-December 2018) doesn’t mention any financial interest from companies regulated by EFSA or related to gene drive technology, it discloses that a close family member receives a lot of funding from the animal feed industry.

John Mumford is a Professor of Natural Resource Management at Imperial College London. His Annual Declaration of Interests, filed at EFSA on 21 January 2019, features several interests that should not have allowed his selection on this panel given EFSA’s independence policy.

  • He is a director at Quilan Dacoma LLC, a family farming business producing cereals, small grains and oil seeds in Oklahoma, USA.

  • He is a “Director of the company Agra-CEAS Consulting Ltd on behalf of Imperial College London, which is a part-owner of the company (with the Informa Group).”

  • One of his “close family members” is employed at the Imperial College through research contracts “from the Gates Foundation related to objective guidance on risk, quality, training and logistical issues affecting GM insect research”. (As Prof. Mumford subsequently describes another interest involving a close family member in the Target Malaria project, chances are that this is in fact the same interest).

  • He has been receiving research funding since 2016 from the Bill & Melinda Gates Foundation for the Target Malaria project for his role as “Responsible to design and implement internal Risk Analysis processes relevant to transgenic mosquito testing and potential use in a research project for malaria control.” According to Pr. Mumford, the funding "accounts for approximately 50% of the research funds managed by me".

- Fabien Nogué is Senior Scientist on Plant and Animal Molecular Biology at France’s Institut National de la Recherche Agronomique (INRA). He is also a member of EFSA’s GMO panel. His declaration of interest was filed at EFSA on 16 June 2019. Among the interests declared:

  • A consultancy contract (discontinued in July 2018) for a French breeding SME, Société Nouvelle des Pépinières et Roseraies Georges DELBARD SAS.

  • Two publicly funded research projects, ANR-11-BTBR-0001 GENIUS and Genetop, which involves the commercial company Biogemma developing GMOs for market approval. The first research project also involves the biopharmaceutical company Cellectis, which develops genome-edited immunotherapeutic treatments for cancer.

  • A research project, GETUP, on the editing of genomes into the Nicotiana Benthamiana plant. MEDICAGO, a biopharmaceutical company, provides 45% of the funding for this project.

  • Nogué participated as an inventor in two patents involving the use of genome editing tools.

  • He is a member of ARRIGE, an international association created in Paris in December 2018 whose goals are to “promote a global governance of genome editing”; to “push forward the scientific, ethical, social, legal and political reflection in the field”; to “foster the development of genome editing technologies within a safe and ethical framework for individuals and for our societies”; and the “dissemination of reliable information regarding genome-editing technology”.

Ernst Wimmer is a Professor at Göttingen University, and Chair of the Department of Developmental Biology. Among the interests listed in his ADoI, filed at EFSA on 15 January 2019, two in particular stand out:

  • A series of consultancy contracts for the International Atomic Energy Agency (IAEA), where he coordinated research projects on the effectiveness of sterile insect techniques (SIT). (This is a comparable approach to what Oxitec is now using; the mass sterilisation of males was previously done using radiation).

  • Inventor and owner of a US patent (6,518,481 B1) on a marker for transgenic insects. Wimmer explains that his patent is used specifically for identifying GM drosophilia (a fly that can be a major orchard pest) and mosquitoes.

  • An exclusive licence with Oxitec Ltd. in the US to use the above-mentioned patent.