Gene drive used to create mosquitoes with potential to stop spread of malaria

A mosquito engineered to carry a gene that can block the malaria parasite has been created in the laboratory, according to study in PNAS. Researchers used CRISPR-Cas9 technology to create a ‘gene drive’ system that spread the anti-malarial gene through a population of the Anopheles Stephensi mosquito, a leading malaria vector in Asia. The gene, which codes for antibodies that combat the parasite, was inherited by almost 100% of the mosquito offspring.

 

Dr. Peter W. Atkinson, Divisional Dean of Life Sciences, Professor of Genetics, College of Natural and Agricultural Sciences, University of California, Riverside (webpage):

Expertise: genetics of medically and agriculturally important insects; molecular-based strategies to genetically control pest insects

“The study is extremely interesting since it demonstrates that gene drive mediated by the Cas9-based system can be achieved in this important pest species in the laboratory. Should it prove to be translatable to field studies and should the effector gene being used prove to significantly reduce the capacity of the mosquito to carry the malaria vector, then it is quite possible that this technology would become an important tool in the control of malaria. As such it would constitute a very, very significant advance in the field. Another advantage of the approach is that it is not eradicating the mosquito species which can open a niche which other mosquitoes could fill. Rather it is potentially replacing the existing genotype with one that has a greatly reduced ability to transmit the pathogen responsible for malaria. The authors are right to invoke the need to consult with regional communities and experts in the application of this technology and that it would form part of much larger insect pest management  and malaria control strategies.”

 

Dr. David O’Brochta, Professor of Entomology, University of Maryland (webpage):

Expertise: genetic technologies for use in insects and the application of those technologies to explore the physiology and genetics that make some mosquitoes excellent vectors of human pathogens

“Gantz et al have replicated their earlier study in laboratory fruit flies, creating a prototype Cas9-based gene drive system in a species of mosquito (Anopheles stephensi), a vector of human malaria. They demonstrate the potential of this technology to potentially eliminate the threat these insects pose as vectors of human parasites.

“The Cas9 enzyme can cut DNA in specific locations and is widely used in genome manipulation or ‘gene editing’. Some of those manipulations can result in Cas9 causing ‘gene drive’ or the rapid spread of Cas9 and associated genes within genomes and through populations. This is a much-discussed and somewhat controversial application of gene editing technology.

“Although only monitoring small laboratory populations of genetically modified mosquitoes over three generations, the investigators saw evidence of efficient ‘spread’ of their gene drive. While the gene drive system contained transgenes for proteins with anti-malaria parasite activity, the ability of the transgenic mosquitoes to support development and transmission of malaria parasites was not evaluated.

“This work is significant because it demonstrates the relative ease and rapidity with which gene drives can be assembled and introduced into a species for which there are well-established methods for introducing genetic technologies. While there was little doubt that this would in fact be the case, Gantz et al. have provided us with a valuable demonstration.

“Scientists have advocated caution in the assembly of ‘autonomous’ gene drive systems as described in this paper. But it should be noted that these studies were conducted in accordance with the emerging community standards among scientists and well outside the normal geographic range of Anopheles stephensi, posing little environmental risk.”

 

Dr. Gregory Lanzaro, Professor, Department of Pathology, Microbiology and Immunology, University of California, Davis (webpage):

Expertise: population genetics of insect vectors of human and animal diseases

“Concern that drug and insecticide resistance are eroding recent successes in managing malaria has drawn attention to alternative approaches, including the use of genetically modified mosquitoes. This new study by Tony James and colleagues marks a significant advance toward the development of this strategy.

“Current strategies for genetically modifying mosquitoes can be divided into two approaches, population suppression, which aims to reduce and ultimately eliminate mosquito populations and population replacement which leaves mosquito populations intact, but introduces genes that render them incapable of transmitting pathogens. The approach described in this paper focuses on population replacement, which has the advantage of minimizing potential environmental impacts that might arise from eradicating mosquito populations (leaving unfilled niches which may be occupied by other vector species or eliminating mosquitoes that may be an important food source for non-target organisms).

“The major advance is the incorporation of an anti-Plasmodium effector gene, in fact two of them, in a construct that includes what appears to be an efficient genetic drive system, CRISPR-Cas9. This new drive system is a major improvement because it can be ‘loaded’ with a relatively large payload, a feature that has proven elusive before now.
“It is clear that a significant amount of work still needs to be done before this system produces a modified mosquito ready for field trials, but the results reported in this paper are very encouraging.”

 

Dr. Anthony M. Shelton, International Professor, Department of Entomology, Cornell University (webpage):

Expertise: Insect ecology and pest management of insects affecting vegetables, Dr Shelton conducts research with genetically engineered diamondback moths

“The results from this paper appear significant and promising for using the novel technique of gene editing to control transmission of the pathogen causing malaria, a devastating disease affecting millions. Genetic engineering of insects is usually focused on their reproduction (e.g. ability to mate, lay eggs, etc.) while this study takes a completely different approach to solving a problem by focusing on the ability of insects to transmit a pathogen. This breakthrough strategy should also hold promise for many other arthropod transmitted diseases that affect humans and crops and for which the use of insecticides continues to be the main tool.

“The authors are certainly justified in their optimism for this approach but clearly state that much more laboratory and field testing is needed. Before open field tests, they need to test their insects in small arenas and/or field cages to determine the potential for it to work on a larger scale. In theory this technology should work in the field, but further tests are needed and only then will the full potential of this breakthrough be realized for the benefit of humanity.”

 

Dr. Megan J. Palmer, Senior Research Scholar and William J. Perry Fellow in International Security, Center for International Security and Cooperation (CISAC), Stanford University (webpage):

Expertise: societal aspects of biotechnology; practices and policies for responsibly advancing biotechnology; biological safety, security, and governance.

Gantz et al.’s study demonstrates the remarkable efficiency with which gene drives might be used to propagate complex genetic traits through populations. Reducing malaria transmissibility in mosquito species may offer important ecological advantages compared to strategies aimed at eradicating mosquito species. Significant work is needed to demonstrate the effectiveness of this tool for preventing parasite transmissibility, its effects on ecosystem health, and how it fits within an overall strategy to combat malaria.

The authors rightly note that the development of regulatory structures and models of ethical engagement with stakeholders are just as (if not more) important as the scientific development of these technologies. This regulatory and engagement work is complex and must be done alongside technology development.

The authors seem to have followed standards recently developed by the relatively small scientific community working on gene drives (including the labs working on this study)[1]. These standards are designed to reduce the risk of unintended consequences from laboratory experiments: using non-native species and working in laboratories designed to prevent their release. We can never eliminate all risks, so management is critical.

Encouragingly, work is being done on these issues. The US government is currently reviewing their framework and processes for regulation of biotechnology products, including mosquitoes engineered to prevent disease vector transmission[2]. The National Academies is also in the midst of a study to examine governance and regulation of gene drives in non-human organisms[3], and has related studies examining risks and benefits of genetic engineering technologies[4].

There are risks with any new technology, and these must be balanced against the risks of not developing improved strategies to combat disease. Continued engagement of experts in science and governance, in partnership with local communities, will be essential to ensuring that tradeoffs can be assessed transparently and accountably.

[1] https://www.sciencemag.org/content/early/2015/07/29/science.aac7932?explicitversion=true

[2] https://www.whitehouse.gov/blog/2015/07/02/improving-transparency-and-ensuring-continued-safety-biotechnology

[3] http://nas-sites.org/gene-drives/

[4] http://nationalacademies.org/gene-editing/index.htm

 

Declared interests (see GENeS register of interests policy):

Dr. David O’Brochta:  Dr. James and I work in the same field, and we are colleagues and friends. We do not have any ongoing projects together and I have no conflicts of interest with any of the authors of this paper.

Dr. Megan J. Palmer: I am colleagues with and have advised investigators that work in this field including Dr. Kevin Esvelt who helped organize the development of gene drive scientific community safety standards.

No further interests declared

 

Reference:

‘Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi’ by Valentino Gantz et al, published in Proceedings of the National Academy of Sciences, on Monday 23 November, 2015.

 

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