Genes in the fast lane: The implications of new gene drive technology – A Canadian Perspective

The Royal Society of Canada is pleased to announce the publication of a new Expert Panel report from its sister academy, the National Academies in the United States. The full report can be accessed online.

Sally Otto

Dr. Sally Otto, FRSC, has kindly provided a Canadian perspective on this report and its relevance to Canada and Canadians. Dr. Sally Otto is a full professor in the Department of Zoology at The University of British Columbia, studying population genetics and evolutionary biology. She develops and analyses mathematical models to study how populations change over time. The aim of her work is to identify when and whether particular evolutionary transitions are possible.

Genes in the fast lane: The implications of new gene drive technology – A Canadian Perspective

“Gene drive” is not a concept familiar to most Canadians.  Yet it is arguably the genetic technology with more social, ethical, and policy implications than any other to emerge in the last decade. The recent report from the National Academy of Sciences (“Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values”) provides important information about what exactly gene drive is, why it is important, and what risks are associated.

Inheritance systems have, by and large, evolved to be fair.  If you have a child, there is nearly an equal chance that your child will carry the gene copy that you inherited from your mother or the one that you inherited from your father.  Most genes in the genome obey this 50:50 rule, the cornerstone of “Mendelian genetics.”  But there are exceptions: genes that tilt the balance in their own favour, becoming inherited by more than half of the offspring. This general phenomenon is known as meiotic drive, and it occurs occasionally in nature by a variety of mechanisms.

“Gene drive” is a form of genetic engineering that incorporates a meiotic drive mechanism whereby a gene copies itself from one parental chromosome to the other.  Originally, only certain types of genes had the potential for this copying, but a recently discovered system (CRISPR) used by bacteria to detect and eliminate foreign DNA allows for almost any genetic target to be used (see Chapter 2 in the NAS report).  This is a game-changing shift in technology.  Gene drive can now be applied to almost any gene in the genome, allowing the engineered gene to spread like wildfire through a population – a “mutagenic chain reaction” (Gantz and Bier, 2015) – as the driving element copies itself to nearly all children each generation.  

The policy implications are huge, with both tremendous potential and risks, as highlighted in the NAS report.  Among the possibilities, gene drive could be used to spread genes that reduce the ability of mosquitoes to transmit parasites (Gantz et al. 2015) or that spread via male mosquitoes but sterilize females (Hammond et al. 2016).  Such systems could stop deadly diseases, including malaria, Zika, and dengue, that kill half a million people worldwide, many of whom are children.  Gene drive could also be used to reduce the spread of invasive species, either sterilizing them or skewing their sex ratios towards males.  In the United States, invasive exotic species are estimated to cost over $120 billion in damages and control costs and pose a major risk factor for many endangered species (Pimentel et al. 2005).

On the other hand, the risks of gene drive following release are also great.  Driven genes could spread beyond the area of interest; eliminating invasive species, for example, outside of areas of concern or perhaps even globally.  Driven genes could also potentially spread beyond the target species due to the occasional hybridization with other species (as has been observed for genes from crops, Ellstrand et al. 2013, and in many natural systems, Harrison and Larson 2014).  Driving elements may also evolve to spread different genetic sequences than originally intended.  Or resistance might evolve, eliminating the intended benefits but leaving the potential for gene drive within natural populations. Applying gene drive to reduce or eliminate the population of a pest or invasive species may often have unintended side effects (e.g., eliminating mosquitoes would, to some extent, reduce food availability for aquatic predators and bats and cause unknown ecological change). Even intentional effects, such as driving a disease-spreading species to extinction, will raise considerable ethical disagreement.

Another risk is the possibility of misuse. While gene drivers have yet to be tested in the field, let alone released in nature, the technology can potentially be applied in any modern molecular biology lab. As regulatory agencies scramble globally to keep up with the recent changes, releases remain possible in countries with weak regulatory frameworks.  Even with strong regulations, the possibility that mavericks anywhere could use the technology is worrisome.

Importantly, driven genes spread via sexual reproduction.  Consequently, species that reproduce on long time scales (over the course of years, including humans) are at low risk; we are likely to be able to detect and mitigate the consequences of drive before the driver spreads far.  The real risks are for short-lived sexual organisms where problems could be widespread before detection and where capturing all affected individuals may be impossible.  

The NAS report describes several means by which risks can be lessened (Chapter 5).  One recommendation is to conduct further research before gene drivers are even considered for release, so that the risks can be better defined and quantified. The report further recommends that all studies be conducted with appropriate means of confinement (i.e., in areas where the organism could not naturally grow) and containment (i.e., with physical or biological barriers preventing spread of that organism). The report also summarizes a number of molecular means to put a break on gene drive, such as the development of “reversal gene drive” (DiCarlo et al., 2015), where drivers work in the opposite direction: replacing the mutated gene with the original sequence.

But minimizing risk will require clear policy statements at all levels of governance (Oye et al. 2014). In Canada, specific guidance on gene drive is currently lacking (a search on canada.ca for “gene drive” returned no relevant documents).  Federal policy statements and fact sheets are needed that would explain what a gene-drive is and how it would be regulated.

Various government departments and agencies in Canada should be involved in regulating gene drive, depending on the intended uses and whether the activities involve research and/or release.  Environment and Climate Change Canada is one department with a legal mandate to govern genetic technology in animals, whether for research or for release (e.g., under the Canadian Environmental Protection Act 1999 and the New Substances Notification Regulations (Organisms)).  Additionally, if a gene drive were to be used for pest control, the Pest Management Regulatory Agency of Health Canada would also have jurisdiction.

Importantly, regulations in Canada that govern the release of any genetically modified organism would also apply to those bearing a driven gene.  This is because Canada has a ‘product not process’ based regulatory system, which automatically covers organisms developed using new technologies.  In particular, any proposed release of gene drive within Canada would be subject to environmental and human health risk assessment.

While current regulations governing genetically modified organism also apply to gene drive, the containment issues for gene drive are different in kind, given that the mechanism involves both a genetic change and the means to spread that change throughout a population.  Furthermore, given the ethical issues involved in altering or eliminating natural species (see Chapter 7 in NAS report), additional levels of ethical oversight are needed for research and field testing that account for the risks of release of organisms bearing gene drivers.  At present, ethics approval must be obtained for University research that uses vertebrate animals or humans, but similar ethics approval should be required for gene drive research in any organism (microbe, plant, invertebrate, vertebrate).  Issues of social justice are also critical here: whose voices are heard when the benefits and the risks are felt far from where gene drivers are developed?

Internationally, the Cartagena Protocol on Biosafety obligates Parties to the Protocol to inform other Parties and the International Biosafety Clearinghouse of any release that might potentially lead to movement across their borders of ‘living modified organisms’ with a potential to affect biological diversity.  Canada has not, however, ratified the Protocol and thus is not at the table to ensure that gene drivers are adequately covered. Given that the benefits and risks of driven genes would not respect borders, it is important that Canada be at the international table to help develop and ensure appropriate global governance.

References

Cartagena Protocol on Biosafety:  https://bch.cbd.int/protocol

Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values. 2016. National Research Council of the National Academies, The National Academies Press, Washington DC, DOI: 10.17226/23405. http://dels.nas.edu/Report/Gene-Drives-Horizon-Advancing/23405 

Ellstrand, N. C., Meirmans, P., Rong, J., Bartsch, D., Ghosh, A., et al. 2013. Introgression of crop alleles into wild or weedy populations. Annual Review of Ecology, Evolution, and Systematics, 44: 325-345. 

Gantz, V.M., and E. Bier. 2015. Genome editing. The mutagenic chain reaction: A method for converting heterozygous to homozygous mutations. Science 348:442-444. 

Gantz, V.M., N. Jasinskiene, O. Tatarenkova, A. Fazekas, V.M. Macias, E. Bier, and A.A. James. 2015. Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi.  Proc. Natl. Acad. Sci. U.S.A. 112(1):E6736-E6743.

Hammond, A., R. Galizi, K. Kyrou, A. Simoni, C. Siniscalchi, D. Katsanos, M. Gribble, D. Baker, E. Marois, S. Russell, A. Burt, N. Windbichler, A. Crisanti, and T. Nolan. 2016. A CRISPR-Cas9 gene drive system targeting female reproduction in the malaria mosquito vector Anopheles gambiae. Nat. Biotechnol. 34:78-83. 

Harrison, R. G., and E. L. Larson. 2014. Hybridization, introgression, and the nature of species boundaries. Journal of Heredity, 105(S1), 795-809. 

Oye, K.A., Esvelt, K., Appleton, E., Catteruccia, F., Church, G., Kuiken, T., Lightfoot, S.B.Y., McNamara, J., Smidler, A. and J. P. Collins. 2014. Regulating gene drives. Science, 345:626-628.

Pimentel, D., Zuniga, R. and D. Morrison, D. 2005. Update on the environmental and economic costs associated with alien-invasive species in the United States. Ecological economics, 52(3): 273-288.