Regulating animals with gene drive systems: lessons from the regulatory assessment of a genetically engineered mosquito

ABSTRACT

For the purposes of conservation or suppression of species, gene drive technology has significant potential. Theoretically speaking, with the release of even relatively few animals with gene drive systems in an ecosystem, beneficial or harmful genes could be introduced into the entire wild-type population of that species. Given the profound impact that gene drives could have on species and ecosystems, their use is a highly contentious issue. Communities and groups have differing beliefs about nature and its conservation or preservation, as well as concerns about the ecological safety of the eradication, replacement or enhancement of particular species of animals by means of genetic engineering. For all those reasons, the rigorous regulation of insects and other animals with gene drive systems is crucial. In this paper, we consider the question of whether the United States Food and Drug Administration is prepared to effectively regulate insects and other animals with gene drives.

KEYWORDS:

• Gene drive
• genetically engineered (GE) mosquito
• risk assessment
• FDA: Oxitec
• Zika

Notes on contributors

As a philosopher with a specialization in ethics, Dr Zahra Meghani’s work is in the area of environmental ethics. She has a number of peer reviewed publications on the normativity of risk assessment of genetically engineered food. In particular, she examines the influence of neoliberalism on the US food regulatory system. Her aim is to identify and develop the theoretical underpinnings of a regulatory review process for genetically modified food that is transparent, unbiased, inclusive and democratic. She is also engaged in health care ethics research. The inequitable distribution of health care resources between different groups at the national and international level is the focus of her research. She is an Associate Professor in the Philosophy Department at the University of Rhode Island.

Jennifer Kuzma is the Goodnight-NCGSK Foundation Distinguished Professor in Social Sciences and co-director of the Genetic Engineering and Society Center at NC State University. Prior to this position she was a faculty member in science and technology policy at the Humphrey School of Public Affairs, University of Minnesota (2003–2013); study director at the National Academies of Science in Washington DC for genetic engineering and bioterrorism (1999–2003); and a AAAS Risk Policy Fellow at the US Dept. of Agriculture (1997–1999). She has over 100 scholarly publications on emerging technologies and governance; and has been studying genetic engineering and its societal aspects for over 25 years. She discovered that bacteria product isoprene, a precursor to natural rubber, during from her PhD work in biochemistry, and her postdoctoral work in plant molecular biology resulted in a publication in the journal Science. She has held several leadership positions, including the Society for Risk Analysis Council & Secretary, Chair of the Gordon Conference on S&T Policy, the FDA Blood Products Advisory Committee, and the UN WHO-FAO Expert Group for Nanotechnologies in Food and Agriculture. In 2014, she received the Society for Risk Analysis Sigma Xi Distinguished Lecturer Award for recognition of her outstanding contributions to the field of risk analysis. She has been called upon in national media for her expertise on genetic engineering policy issues, including recently in the Washington Post, Scientific American, New York Times, 2015 World’s Fair exhibit, Nature, and National Public Radio.

Notes

1. CRISPR denotes Clustered Regularly Interspaced Short Palindromic Repeats. Cas9 is a nuclease that makes cuts in DNA next to CRISPR sequences. These have been engineered and harnessed for gene editing.

2. Plants pests are to be regulated by the United States Department of Agriculture (USDA).

3. We use ‘GE’ in this paper to indicate organisms manipulated in the laboratory by modern biotechnology methods such as recombinant DNA technology and gene editing. Note that ‘genetically modified’ (GM) is used often in countries outside of the US.

4. The Oxitec mosquito that is the subject of this paper is currently under the regulatory authority of the EPA. The FDA had originally laid claim to regulatory power over the GE mosquito on the grounds that the rDNA construct introduced into the mosquito qualified as a drug. In February 2016, Oxitec submitted the draft EA that it had prepared to the agency. A month later, the agency issued a preliminary FONSI statement. (This paper was written in the wake of the issuance of the draft EA and FONSI.) After soliciting public comments on the draft Environmental Assessment and preliminary (FDA) FONSI, in August 2016, the FDA posted on its website its (final) Environmental Assessment and FONSI. Then, in October 2017, the FDA issued the guidance document, ‘Clarification of FDA and EPA Jurisdiction Over Mosquito-Related Products.’ In it, the agency ceded authority over GE mosquitos, including the Oxitec mosquitos, which have a pesticide function to the EPA. This change of regulatory jurisdiction for the GE mosquito was justified on the grounds that in 1975 Congress had amended the Federal Insecticide, Fungicide and Rodenticide Act’s definition of ‘pesticide’:

to exclude any article that is a ‘new animal drug’ within the meaning of the FD&C Act. Since the FIFRA definition of pesticide was amended in 1975, EPA has registered, as pesticides, articles that control the population of mosquitoes by killing them or interfering with their reproduction, which is consistent with FDA’s and EPA’s general agreement that articles or categories of articles that control the population of mosquitoes are most appropriately regulated as pesticides. This general agreement arises from a careful consideration of Congressional intent. (FDA 2017, 5)

Presumably, both regulatory agencies were aware of the 1975 change to FIFRA, but it was only in October 2017 that the FDA ceded regulatory authority over the GE mosquito to the EPA.

5. We do not focus on whether risk assessment is itself appropriate and sufficient for making decisions about emerging technologies; others have written about that question elsewhere (Wickson 2007). Instead, we acknowledge that at least practically, risk assessments through the federal agencies will be the norm for decision-making for the foreseeable future. White House executive orders and federal agency policies give risk assessment a principal role in US regulatory policy.

6. This section draws on Meghani (2014).

7. For a carefully detailed account of the change in the FDA’s risk assessments practices, see Hilts (2003).

8. According to Hilts, beginning in the 1980s, FDA reviewers routinely ‘offered detailed advice (to developers of pharmaceuticals) on what studies were needed and how they should be designed’ (2003, 228). Prior to the 1980s, FDA reviewers ‘were not permitted to give company scientists guidance about what evidence would be sufficient to prove a drug’s safety and effectiveness’ (2003, 228).

9. For a critique of the ‘clarification' process see Kuzma (2016).

10. While there are currently no guidelines for the risk assessment of animals with gene drives (as mentioned above), both the NASEM (2016) and the WHO use guidelines for ‘regular’ GE insects such as the OX513A mosquito to consider risk assessment for gene drives in animals.

11. A synthetic gene for the tetracycline transcriptional activator variant protein (tTAV) is introduced into the mosquito and acts as a tetracycline-regulated switch. High level expression of tTAV is deleterious to cells, as it represses normal transcriptional function. In the presence of tetracycline, tTAV is repressed, so that the GE mosquito can be reared in the laboratory. In the absence of tetracycline, tTAV is active and kills the cells. The assumption is that the non-laboratory environment does not contain enough tetracycline for the GE mosquitos to survive.

12. In November 2016, Florida residents approved the release of the GE mosquitos on the basis of a public referendum but the town of Key Haven that was the site of the release rejected it. In the US, as of October 2017, no field trial of OX153A has taken place in the US.

13. Needless to say, the decision to classify the rDNA construct that is lethal to the animal in which it has been introduced (and its progeny) as a new animal drug has the odd result of the agency attempting to ascertain its safety for that organism because by law the FDA is obligated to determine whether new drugs are safe for the entities to which they are prescribed.

14. See for instance Oye et al. (2014) about other important variables that should be measured.

15. The exceptions are the GE mosquitos that are intended to function as pesticides.

Additional information

Funding

The workshop was funded by the National Science Foundation – SES and Science in Society Program [grant number 1533990] with additional co-funding by the Genetic Engineering and Society Center (GES) at North Carolina State University (NCSU) and the Center for Nanotechnology in Society at Arizona State University. The views, however, are those of the authors and not these institutions.