What is gene drive?
The term ‘gene drive’ refers to a pattern of inheritance in which a certain gene is preferentially transmitted to the next generation. For example, many plants and animals have two copies of each of their genes, having inherited one from their male parent and one from their female parent. For a gene that does not exhibit drive, each of those copies is equally likely to be passed to the next generation. For a gene that displays ‘gene drive’ one of those copies would be preferentially passed to the next generation. This pattern of preferential inheritance from generation to generation means that in a relatively short time genes displaying gene drive can become highly prevalent in a population.
While the specific term ‘gene drive’ only came into use at the beginning of the 21st century, the genetic phenomenon referred to as drive was first recognized early in the 20th century as a natural occurrence in many organisms. Researchers first expressed the possibility of using drive systems to control pest insects in the 1950s.
A gene drive is a type of genetic engineering technique that modifies genes so that they don’t follow the typical rules of heredity. Gene drives dramatically increase the likelihood that a particular suite of genes will be passed onto the next generation, allowing the genes to ...
You may also like to explore this section of the Virtual Institute
Why is there an interest in ‘gene drive’?
Scientists have proposed ways to use the preferential inheritance that characterizes ‘gene drive’ to develop solutions for previously intractable threats to public health, food security and biodiversity. For example, gene drive technologies have been proposed to address problems in public health such as the transmission of arthropod-borne pathogens, problems in agriculture caused by insect pests, weeds and plant pathogens, and problems in conservation caused by invasive species. Adding to this interest is the fact that recent advances in biotechnology are allowing researchers to test their ideas for using gene drive to address these important problems.
Who invented gene drive?
Gene drive is a genetic phenomenon found in nature and is not an “invention”. The term refers to a pattern of inheritance that is found commonly in nature whereby a form of a gene (an allele) is preferentially transmitted during sexual reproduction compared to other alleles of the same gene. Using examples of gene drive found in nature as models, scientists are assembling genes and DNA sequences in the laboratory which, when introduced into the genome of an organism, will mimic natural gene drive. Some of these engineer gene drive systems might be useful for introducing genetic traits into certain insect , animal or plant populations for the benefit of public health, conservation or agriculture.
Gene Drive & Genetic Biocontrol Timeline. This section of the Virtual Institute will also be helpful in tracing the genesis and history of the ideas and technologies currently being developed. Contemporary genetic biocontrol research and development, including gene drive, is a culmination of work beginning in the early 20th century. This collection of knowledge from the Virtual Institute’s knowledgebase highlights notable research in the history of genetic biocontrol technology.
Are all gene drives constructed using CRISPR/Cas gene editing systems?
No. Functional gene drive technologies have been assembled and tested in the laboratory that do not use any components of CRISPR/Cas gene editing systems. Many do, however, and this is because Cas gives researchers and engineers an unprecedented ability to control the precision and species specificity of the technology.
Here are some examples of CRISPR/Cas-free gene drive systems:
Population replacement in Culex-fatigans by means of cytoplasmic incompatibility .2. Field cage experiments with overlapping generationsC. F. Curtis, Bulletin of the World Health Organization, 53:107-119. 1976.
Three experiments were carried out in field cages to test the principle of " transport" of a desirable gene or chromosome into a wild Culex fatigans population as a result of the sterility in cross-matings associated with cytoplasmic incompatibility. Cycling populations of Delhi ...
Experimental population-genetics of meiotic drive systems .1: Pseudo-Y chromosomal drive as a means of eliminating cage populations of Drosophila melanogasterLyttle, TW, Genetics, 86:413-445. 1977.
The experimental population genetics of Y-chromosome drive in Drosophila; melanogasier is approximated by studying the behavior of T(Y;S),SD lines.; These exhibit “pseudo-Y” drive through the effective coupling of the Y chromosome; to the second chromosome meiotic drive ...
Transporting marker gene re (red eye) into a laboratory cage population of Aedes-aegypti (Diptera Culicidae), using meiotic drive at MD locusR. J. Wood, L. M. Cook, A. Hamilton and A. Whitelaw, Journal of Medical Entomology, 14:461-464. 1977.
An attempt has been made to use the meiotic drive gene MD to transport a marker re (redeye) into a laboratory population of the mosquito Aedes aegypti. The experiment produced an increase in re frequency, but also indicated that this gene has unexpectedly high fitness in the ...
What is CRISPR-Cas?
The term “CRISPR-Cas ” has become synonomous in popular science writing and reporting with ‘gene editing’, a collection of genetic modification technologies that enable the alteration of genomes with a degree of precision and accuracy greater than previous technologies.
Technically, “CRISPR-Cas” refers to well defined regions of bacteria genomes whose function is to defend the bacterial cell from viral infections. These regions consist of two parts. One part consists of a cluster of regularly interspersed palindromic repeated sequences of DNA (CRISPR). The second part consists of a closely linked series of genes that are associated with the CRISPR region (CRISPR-associated genes) and encode for enzymes that can, under some conditions, cleave DNA at specific locations.
There are many explanations of CRISPR-Cas. Here are a few that are a good starting point.
A short video that simply explains what CRISPR is and how it is used for gene editing. Simple language and highly accessible.
What is the difference between gene editing and gene drive?
Gene editing refers to changing an organism’s DNA while gene drive refers to a pattern of inheritance. The term ‘gene editing’ is used to describe relatively precise alterations in genomes that are accomplished using any one of a number of tools sometimes referred to as molecular scissors (endonucleases). A popular and powerful version of molecular scissors for gene editing is the CRISPR-Cas system. MORE ABOUT EDITING–>
Gene editing is being used for a variety of purposes. One popular mechanism to engineer gene drive in the laboratory utilizes a component of the CRISPR-Cas gene editing system. There also are other ways by which preferential inheritance patterns that are the hallmark of gene drive can be achieved by researchers using other biotechnology tools and methods. MORE ABOUT GENE DRIVE–>
What is risk analysis?
Risk analysis is a structured process for identifying, assessing, and managing potential problems, which helps to achieve the appropriate level of safety. It begins by identifying harms that might result from the particular activity or event that is under consideration. This is followed by a thorough consideration of potential pathways to harm for human or animal health, the environment, or socioeconomic welfare. It then considers the likelihood that the harm will occur and the likely consequences under scenarios relevant to the planned actions, which will characterize the risks. Once the risks are assessed, plans are made to avoid or reduce any identified risks through risk management. Finally, the risks and management plans are communicated to involved decision-makers and stakeholders to enable them to understand these risks and to decide upon their acceptability. The process culminates in decision-making by national authorities and stakeholders about the acceptability of any remaining risks in the context of potential benefits.
(Ref: WHO Guidance Framework for testing genetically modified mosquitoes https://www.who.int/tdr/publications/year/2014/guide-fmrk-gm-mosquit/en/;James et al. 2018 Am J Trop Med Hyg 98(6-Suppl):1-49 http://www.ajtmh.org/content/journals/10.4269/ajtmh.18-0083).
What is risk assessment?
Risk assessment is an important part of the risk analysis process. The concept of risk takes into account both the likelihood and magnitude of harm arising from an identified hazard (an unwanted event that would have a negative impact, or harm). Risk assessment is an objective process to identify what hazards are relevant and how significant the risks are.
What potential hazards are posed by gene drive-modified mosquitoes?
Health hazards that have been identified as priorities for testing include the potential for the genetic modification to cause increased abundance of mosquito species that carry malaria; alterations that would result in an increased ability to transmit pathogens; alterations that would reduce the ability to control the mosquitoes with conventional methods; increased allergenicity or toxicity; and increased virulence of pathogens carried by the mosquito. Environmental hazards identified as priorities include the potential for the genetic modification to result in: spread of the modification to other species that would cause harm to the ecosystem; indirect harm to other species that depend on the modified mosquito species for some essential service; increase in harmful competitor species; and harmful higher order effects to the ecological community.
(Ref: James et al. 2018 Am J Trop Med Hyg 98(6-Suppl):1-49 http://www.ajtmh.org/content/journals/10.4269/ajtmh.18-0083).
Are gene drive modified mosquitoes intended to cause species extinctions?
Gene drive mosquitoes are not intended to cause extinction of the mosquito species in which they are being used. Mosquito eradication (the complete elimination of a species from an environment) or extinction (the complete absence of any living representative of a species) are not necessary to achieve the public health outcomes for which gene drive technologies are being researched and developed.
Although one type of genetically modified mosquito technology is intended to suppress populations of the targeted mosquito species by reducing reproductive rates, the primary objective is to reduce or eliminate disease transmission. This can be done by reducing the numbers of the target mosquito species to levels too low to maintain the life cycle of the pathogen, but does not require eradication or extinction of species.
Are gene drive technologies currently being used?
Currently (2020) gene drive technologies are only being tested in the laboratory as part of ongoing research and development efforts. No drive technologies are being used outside the laboratory.
Are gene drive technologies safe?
The safety of gene drive technologies is an important concern shared by all stakeholders. Gene drive technologies are intended to be used in the environment and their environmental safety will be evaluated on a case-by-case basis by developers as well as national regulatory authorities. Safety is evaluated by a process called risk analysis, which takes into account both the characteristics of the technology and those of the environment in which it will be used. This process will help governments and citizens determine whether the risks associated with a technology are acceptable.
Are gene drive technologies unprecedented?
Gene drive occurs frequently in nature without any human intervention. Gene drive technologies being investigated today are the direct descendants of ideas and technologies that first emerged during the middle of the 20th century and which have been under investigation since then. For example, in 1947, Vanderplank tested use of a naturally-occurring gene drive system to control a species of tsetse fly for prevention of African trypanosomiasis.
For a historical perspective on genetic biocontrol and gene drive research and development visit this section of the Virtual Institute.
Are gene drives ‘unnatural’?
No. Gene drive occurs frequently in nature without any human intervention. Genomes of all organisms contain genes that display gene drive; For example, transposons or ‘jumping genes’ are the Nobel Prize-winning discovery of Dr Barbara McClintock in the middle of the 20th century and display gene drive. Transposons now are known to be common and abundant in the genomes of all organisms and their importance and significance is well documented. Many other naturally occurring mechanisms creating preferential inheritance of genes, alleles and chromosomes also exist.
Are organisms with gene drive genetically engineered?
Gene drives occur in nature. In fact, all genomes that have been examined to date are found to contain natural ‘gene drives’. However, terms such as ‘gene drive organisms’ and ‘gene drive’ often are used to imply products of genetic engineering.
How do mosquitoes transmit disease?
Female mosquitoes transmit parasites and pathogens when they feed on the blood of an animal. Female mosquitoes require nutrients found in blood to support the development of their eggs. Males have no such requirement and therefore, only female mosquitoes bite humans or animals. If the human or animal they bite is infected with pathogens or parasites that can be transmitted by mosquitoes, the female mosquito can acquire them when she takes a blood meal. She may then be able to pass that pathogen to the next human or animal she bites through her contaminated saliva, some of which she expels into the host at the beginning of blood feeding.
There are many limitations on this scenario. To be transmitted to the next host, the pathogen must survive the mosquitoes’ digestive system, enter its circulatory system and then its salivary glands. There are many human blood-borne pathogens, like HIV and hepatitis viruses, that cannot survive in mosquitoes. Moreover, the pathogen and the species of mosquito must be compatible – only certain pathogens can survive and multiply in certain mosquito species. For example, human malaria parasites only can be transmitted by Anopheles mosquitoes. Finally, the pathogen also must be compatible with the human or animal host. Some animal pathogens cannot live in humans, and vice versa. For example, certain malaria parasites that cause disease in birds cannot infect humans.
Aren’t mosquito-borne diseases like malaria and dengue transmitted by many different mosquito species, and wouldn’t one have to release genetically modified versions of all of them?
Of the approximately 3500 species of mosquito about 70 species of mosquito have been reported to transmit malaria worldwide, but they are all not equally good as vectors, resulting in some being much more important than others in spreading disease. For example, one of the reasons why Anopheles gambiae is such a dangerous vector of human malaria in Africa is because of its almost exclusive preference for biting humans whereas other vectors tend to also bite animals in order to obtain the blood needed for their reproduction. Thus, control of this powerful vector in Africa will have a disproportionately large impact on malaria transmission. Likewise, dengue is primarily transmitted by Aedes aegypti mosquitoes, so targeting just these mosquitoes could dramatically reduce disease transmission.
Aren’t vaccines going to solve the problems of mosquito-borne diseases like malaria and dengue?
Vaccines are important tools against several infectious diseases, but unfortunately, despite decades of effort, not yet for malaria and dengue. Malaria and dengue are very challenging diseases to control and there is little doubt that successful control and/or elimination will require multiple different tools, with vector control remaining important with or without available vaccines.
Can a gene drive created in mosquitoes be transmitted to humans ?
This is extraordinarily unlikely because it would require a series of highly improbable events to occur:
First, analyses of the genomes of primates (including humans) have not revealed the presence of any insect genes, indicating that a transfer of genes from mosquitoes to humans (horizontal gene transfer) despite the long evolutionary history of some mosquitoes interacting with primates has been very rare, if it has occurred at all.
Second, it would also be highly unlikely that if naked DNA were transferred in a mosquito bite, that the DNA with all the elements required for a functional gene drive could make its way inside a human cell, and even less likely that the cell would be a cell responsible for making sperm or eggs.
Third, most gene drive systems are constructed so that the gene drive is active in only certain cells of the reproductive system of the mosquito and at a certain time during the formation of sperm or eggs. These temporal and spatial constraints are important and are achieved through the use of DNA sequences the exhibit these properties only in the species from which they were obtained. These molecular components of the gene drive are highly unlikely to function within a human cell as they do in mosquito cells.
The fact hat each of these events individually have extremely low improbable means that taken together the probability of a functional gene drive being transferred from the cells of mosquitoes to the cells of humans is exceedingly low.
Can gene drive technologies be used to spread genes through human populations?
No applications for the types of gene drive technologies being developed for use in mosquitoes have been described for humans, nor are any likely. While it may be technically feasible to assemble a gene drive system that would function in human cells, that system would be highly inefficient because humans have a relatively long generation time (20 years) and few offspring (global average fertility rate is ~2.5 children per woman).
“Gene editing’ and ‘gene drive’ are often confused and conflated. Gene editing has many possible therapeutic applications in humans and is one of many gene therapy technologies. Gene therapies involves only the genetic alteration of somatic cells and will not be transmitted to the next generation. An example of ‘gene editing’ as ‘gene therapy’ can be found here.
Can you stop mosquito gene drive technologies once the technology-containing mosquitoes have been released?
Some types of gene drive technologies are intended to be self-limiting; that is they are designed so they will not spread indefinitely but will stop spreading when known conditions are met. However, researchers also are investigating ways by which a self-sustaining drive could be controlled or eliminated if desired. There are several strategies that theoretically might be employed to stop mosquito gene drive technologies following their release into the environment. If they have not spread too far, gene drive containing-mosquitoes might be eliminated from an environment using chemical insecticides or by releasing large numbers of mosquitoes carrying natural or engineered DNA sequences that are resistant to the gene drive. Another possibility is that the initial gene drive might be disabled or removed from the mosquitoes by releasing a second gene drive technology specifically designed to target the first technology. Alternatively, gene drive technologies that rely on the gene editing enzyme Cas might be stopped using small molecules that specifically inhibit the enzyme, thereby shutting off the gene drive. As yet, none of these have strong evidence to support their effectiveness but this is an active topic of research.
(Ref: While technical in nature these publications discuss various options (links in VI)
- Marshall, J. M. A., Omar S. Can CRISPR-based gene drive be confined in the Wild? A question for molecular and population biology. ACS Chemical Biology 13, 424-430, doi:10.1021/acschembio.7b00923 (2018).ations consider the topic
- Esvelt, K. M., Smidler, A. L., Catteruccia, F., and Church, G. M. (2014) Concerning RNA-guided gene drives for the alteration of wild populations, eLife 3, DOI: 10.7554/eLife.03401.
- Champer, J., Buchman, A., and Akbari, O. S. (2016) Cheating evolution: engineering gene drives to manipulate the fate of wild populations. Nat. Rev. Genet. 17, 146−159.
- Vella, M. R., Gunning, C. E., Lloyd, A. L., and Gould, F. (2017) Evaluating Strategies For Reversing CRISPR-Cas9 Gene Drives, Sci. Rep., DOI: 10.1038/s41598-017-10633-2.
- Modeling the mutation and reversal of engineered underdominance gene drivesBy: Edgington, Matthew P.; Alphey, Luke S.JOURNAL OF THEORETICAL BIOLOGY Volume: 479 Pages: 14-21 Published: OCT 21 2019
- Catch Me If You Can: A Spatial Model for a Brake-Driven Gene Drive Reversal By: Girardin, Leo; Calvez, Vincent; Debarre, FlorenceBULLETIN OF MATHEMATICAL BIOLOGY Volume: 81 Issue: 12 Pages: 5054-5088 Published: DEC 2019)
Do all gene drives spread?
They all have the potential to spread to some extent. The defining characteristic of gene drive is preferential transmission to the next generation, and this will result in the gene drive element increasing in frequency (spreading). Some gene drive technologies are designed with temporal or spatial limitations on the degree of anticipated spread, and therefore the gene drive is expected to remain more localized.
What is biocontrol?
Biological control uses living organisms to reduce and control populations of pest organisms. In classical biological control the pest organisms can be invasive animal or plant species with no or few natural enemies in its new location, and the biological control agent is a natural enemy of the pest species imported from the pest’s home range. Depending on the nature of the pest species, control agents might be pathogens, insects, grazing or predatory animals. There are other biological control strategies that do not involve importation of natural enemies and focus on augmenting or promoting populations of native species that can control the pest.
What is genetic biocontrol?
This is a form of biological control in which genetic variants or genetically modified forms of a target species serve as controlling agents in some way so that the threat posed by the target species is reduced or eliminated. For example, the target might be a pest species or a vector species that transmits human, animal or plant diseases.
What are some examples of genetic biocontrol?
The most well developed and widely used genetic biocontrol is the Sterile Insect Technique (SIT). This is an insect control strategy devised in the middle of the 20th century in which a target species of insect is mass-reared to large numbers and then sterilized using gamma-rays before being released into wild populations of the target species. Preferably only sterilized males are released and when they find and mate with a fertile wild female, the female will produce no viable offspring although her drive to find a mate and reproduce has been satisfied. Regular repeated releases of sterile males will result in a reduction of the target population and in some cases its local elimination. Other examples of genetic biocontrol include the use of a hybrid incompatibility phenomenon wherein mating between two strains of a species results in a reduced number of offspring as compared to mating between individuals of the same strain.
Does genetic biocontrol always use organisms that are genetically modified?
If one defines genetic modification as a change in the genetic material that was created through the use of modern biotechnology (genetic engineering), then genetic biocontrol does not always use organisms that are genetically modified. The genetic make-up of an organism can be altered using irradiation as is the case for the Sterile Insect Technique, or even selective breeding. However, there are variants of the Sterile Insect Technique that involve the release of insects that have been modified in the laboratory (genetically engineered) to effect similar changes.
Does the Convention on Biological Diversity have a position on the research, development and use of gene drive technologies?
The Convention on Biological Diversity (CBD) is an international agreement that aims to conserve biodiversity. Most countries in the world are Parties to this agreement. The CBD considers organisms that contain synthetic gene drives as part of the broad category of research called Synthetic Biology. Furthermore, it considers organisms with synthetic gene drives as Living Modified Organisms (LMOs; more familiarly referred to as Genetically Modified Organisms, or GMOS). Since gene drive-modified organisms are LMOs, the CBD considers the Cartagena Protocol on Biosafety (CPB) as the appropriate umbrella under which policies regarding their transboundary movement are developed, including risk assessment. The CBD has thus far recommended that a precautionary approach should be taken with regard to decisions on activities in the field.
(Ref: Convention on Biological Diversity https://www.cbd.int/; Report of the Ad Hoc Technical Expert Group on Risk Assessment, Montreal, Canada, 15 April 2020, https://www.cbd.int/doc/c/a763/e248/4fa326e03e3c126b9615e95d/cp-ra-ahteg-2020-01-05-en.pdf )
Have any biocontrol measures been applied to mosquitoes?
Yes, there are several biological control approaches that can be and are being taken against mosquitoes. Among the more conventional biocontrol approaches, fish such as those in the genus Gambusia (aka “mosquitofish”) have safely played an important role in controlling mosquitoes for decades. Their use to control mosquitoes in rice cultivation areas is well documented. Some isolates of the bacteria Bacillus thuringiensis are widely used to control mosquitoes and are sold for use by gardeners and property owners, who prefer these to chemical pesticides. Fungi such as Beauveria bassiana and Metarhizium anisopliae are readily available biological control agents for use against mosquitoes. For example, Beauveria bassiana is an active ingredient in some of the mosquito control products of In2Care, a mosquito trap developed to protect humans against mosquitoes that transmit the Zika, chikungunya, yellow fever and dengue viruses.
Three versions of the Sterile Insect Technique are being field tested in Aedes aegypti, a mosquito responsible for transmitting dengue, yellow fever, Zika and other human pathogenic viruses. These techniques include a version employing radiation sterilization by the Insect Pest Control Section of the Joint FAO/IAEA Program, of the United Nations, another called the Incompatible Insect Technique exploits certain effects of the intracellular bacteria Wolbachia, which is being developed and tested by the company MosquitoMate. The company Oxitec has developed genetically engineered mosquitoes which carry genes that inhibit the survival of offspring similarly to SIT. .
Biocontrol technologies that are heritable also are being assessed. The World Mosquito Program is using Wolbachia bacteria in a way that is passed on to offspring, and immunizes the mosquito Aedes aegypti populations against infection by dengue, yellow fever and Zika viruses. Oxitec has developed genetically engineered mosquitoes which are fertile and contain genes that inhibit the survival of female offspring when they mate with wild mosquitoes.
Have governments taken formal positions on gene drive technologies ? What are their positions?
Governments have not taken formal positions to support the deployment of the gene drive technologies, nor to prevent research and development. However, the African Union High Level Panel on Emerging Technologies has formally supported research that would explore the use of this technology to control malaria. Several academic societies and government agencies have published recommendations for risk assessment of gene drive-modified organisms.
(Ref: AUDA-NEPAD https://www.nepad.org/publication/gene-drives-malaria-control-and-elimination-africa; http://nepad-abne.net/wp-content/uploads/2020/07/Position-Paper-on-Integrated-Vector-Management_Strengthening-AU-Members-Regulatory-Capacities-for-Responsible-Research-Towards-Elimination-of-Malaria-in-Africa_v2.pdf
How are research, development and use of gene drive modified mosquitoes regulated?
The regulation of research, development and use of gene drive modified mosquitoes will be determined by national laws and policies, which may differ from country to country. In countries that are Parties to the Cartagena Protocol, gene drive modified mosquitoes will be regulated as genetically modified organisms through a biosafety mechanism established by the national biosafety law. It is expected that Ministries of Health and Ministries of Environment will be involved. In the US, which is not a signatory to the Cartagena Protocol, genetically modified mosquitoes aimed at reducing population size currently are regulated by the Environmental Protection Agency, while genetically modified mosquitoes that aim to reduce vectorial capacity are regulated by the Food and Drug Administration.
(Ref: Cartagena Protocol on Biosafety https://bch.cbd.int/protocol/background/)
How can a gene drive spread if it causes a decrease in the fitness of the organism that carries it?
Decreased fitness results in fewer offspring contributing to the next generation, but if all or most of those offspring possess the gene drive, then the gene drive can still spread. As long as the advantage gained from the gene drive is greater than any associated fitness disadvantage it might cause, the gene drive is predicted to continue to increase in prevalence and spread. If the net advantage conferred by gene drive is low, however, the rate of spread could be quite low.
How can developers of gene drive technologies know what the gene drives will do after they are released into the environment?
There are uncertainties associated with any new technology. That is why a phased testing approach is strongly recommended for the development of genetically modified mosquitoes containing gene drive systems. Release of gene drive containing mosquitoes into the environment must be preceded by extensive research and testing in the laboratory. Their behavior will be studied in the insectary and/or large indoor cages. In addition to empirical evidence coming from experiments, mathematical modelling will play an important role in predicting the behavior following release. It is recommended that a comprehensive all-hazards risk assessment be performed before beginning field testing of any kind.
If releases are approved, they should begin at a very small scale under conditions that will minimize risk. Efficacy and safety for health and the environment must be monitored at all phases of testing.
(Ref: James et al. 2018 Am J Trop Med Hyg 98(6-Suppl):1-49 http://www.ajtmh.org/content/journals/10.4269/ajtmh.18-0083; James et al 2020 Vector-borne Zoonotic Dis 20:237-251 https://www.liebertpub.com/doi/full/10.1089/vbz.2019.2606).
How could you use gene drive to improve public health?
Vector-borne diseases cause an estimated 700,000 deaths per year worldwide. Research indicates that gene drive technologies have unique potential to address public health challenges posed by vector-borne diseases, especially those transmitted by mosquitoes. Gene drive technologies could, for example, help to reduce the toll of mosquito-borne diseases either by reducing the fertility of vector mosquitoes, so fewer will be present to spread disease, or by decreasing their ability to carry pathogens. In either approach, gene drive would spread the trait from one generation to the next, eventually lessening the number of mosquitoes that can infect people.
Not only might gene drive technologies reduce the incidence of infection in areas where there is active transmission of mosquito-borne diseases, but potentially they could prevent the appearance of these diseases in areas that are threatened with disease introduction or re-introduction
How does gene drive relate to genetic biocontrol?
Gene drive systems are a type genetic biocontrol in that genetic variants or genetically modified forms of a target species serve as controlling agents in some way so that the threat posed by the target species is reduced or eliminated. In the case of gene drive technologies, the genetic variation or genetically modified form of the target species is fertile and able to efficiently pass the genetic variation responsible for the biocontrol effect to subsequent generations so that all or most of the individuals in a population carry the variation.
How do we know that people in disease-endemic countries will want to use genetically modified mosquitoes?
Genetically modified mosquito technology has only recently progressed to the stage where the different approaches can be described precisely enough to be able to ask the relevant questions of those who may experience their benefits and risks. Formal surveys of attitudes in disease-endemic countries are underway and are a priority for future research. Although there has been significant resistance to genetic modification technologies in general, early results suggest that people in disease endemic countries are open to the concept of genetically modified mosquitoes for public health.
(Ref: African Centre for biodiversity https://www.who.int/news-room/fact-sheets/detail/malaria; Marshall et al. 2010 Malaria Journal 9:128 https://malariajournal.biomedcentral.com/articles/10.1186/1475-2875-9-128; Finda et al., Malaria Journal 2020 19:164
Who is the Virtual Institute for?
The GeneConvene Virtual Institute is for anyone interested in genetic biocontrol generally and gene drive technologies specifically. The content found in the Virtual Institute ranges from primary research reports written by researchers to easy-to-understand media articles, infographics and videos and is intended to be useful to everyone with interests in these areas of applied genetics.
How is content identified for inclusion consideration?
The GeneConvene Virtual Institute has 3 main mechanisms by which it identifies potential content.
- The GeneConvene Global Collaborative uses digital data mining tools to monitor scholarly and media publications and public reports related to genetic biocontrol and gene drive technologies.
- The Virtual Institute has Content Advisors spanning different domains of interest and located across the globe who alert the Virtual Institute to potential content as they encounter it.
- The Virtual Institute also relies on content alerts and suggestions from users.
How will the perspectives of local individuals and communities at testing sites be taken into account?
Field testing of genetic biocontrol technologies must be guided by the widely recognized informed consent goal of protecting the interests of those who will be affected by the research. Testing plans will be overseen by an institutional ethics committee (or review board), whose role is to protect the rights and welfare of research participants. Researchers must discuss their testing plans with the community at the proposed field site, allowing opportunity for community members to ask questions or express concerns. These concerns should be considered in the risk assessment. An all-hazards risk assessment should take socioeconomic risks, such as any potential negative impact on basic living conditions, social structure, public health or livelihood, into consideration.
Researchers must provide answers to community questions or adjust their plans in response to the concerns and seek community authorization for the study to be undertaken. The mechanism for community deliberation and authorization should be determined by the community itself according to its norms. Individual informed consent is a pre-requisite if personally identifiable information or biological specimens will be collected. Public consultation is a requirement for approval of activities with GMOs in country legislation, and informed consent is at least a standard principle if not a legal requirement for work research involving humans. These elements are prerequisites for regulatory approvals.
(Ref: World Health Organization https://apps.who.int/iris/bitstream/handle/10665/44783/9789241502948_eng.pdf;jsessionid=E6339F03F92F9D714F34F905E0884750?sequence=1; WHO Guidance Framework for testing genetically modified mosquitoes https://www.who.int/tdr/publications/year/2014/guide-fmrk-gm-mosquit/en/;James et al. 2018 Am J Trop Med Hyg 98(6-Suppl):1-49 http://www.ajtmh.org/content/journals/10.4269/ajtmh.18-0083).
If a gene drive technology in one species gets into another species will it display gene drive in the second species?
For an engineered gene drive to function, a small number of genes contained within the gene drive element need to be expressed in specific cells and at specific times within the host organism. The genetic switches that turn those important genes on and off at the right time and in the right place will not function in all organisms, particularly organisms distantly related to the host organism. So not only will the gene drive need to get into the right cells of a second organism (germ cells – cells that produce sperm or eggs) so that it has the possibility of being transmitted to subsequent generations, but all of the components of the gene drive will need to function properly in the new host (see Gene Drive Basics)
Is anyone using gene drive right now?
Gene drive technologies actively are being researched and developed, but have not yet been used outside of laboratories.
Is it ethical to cause a species to go extinct?
Species extinction occurs when there are no living representatives of a species anywhere in the world. This is not an intended outcome nor is it a likely outcome of any ongoing genetic biocontrol technology research and development effort. It is far more likely that while local elimination may be observed, natural barriers to gene flow will prevent gene drive systems from spreading through an entire species. However, in the improbable case that gene drive did affect the entire target species in the wild, the parent species still could be maintained in the laboratory. The ethics of permanently modifying a species or eliminating it in the wild can be debated, but this must be considered in the context of the benefits to be gained from improved public health. There is a rich literature on the ethics of pest control, disease eradication and species extinction and the reader is encouraged to explore it and come to their own conclusions.
(Ref: Pugh, J. 2016 J. Med. Ethics 42, 578-581 https://jme.bmj.com/content/42/9/578;
Antonelli, A. & Perrigo, A. 2018 Nat. Ecol. Evol. 2, 581-581 https://www.nature.com/articles/s41559-018-0500-z).
Is the expectation of autonomous transboundary movement by gene drive-modified mosquitoes unprecedented?
There are established precedents for autonomous transboundary movement. Classical biological control, in which non-native insects are released for the purpose of reducing or eliminating an insect of economic or public health importance, has been practiced for well over a century. Biological control agents are expected to become permanently established over large areas irrespective of political borders. Some wildlife vaccination programs seek to make non-hereditary genetic modifications in free-ranging species such as racoon and fox to reduce the risk of rabies transmission to people. The possibility for autonomous dispersal, for example of pollen or spores, also has been a consideration for other GMOs.
Is the Sterile Insect Technique used against mosquitoes?
Efforts are under way and progress is being made in developing Sterile Insect Technique (SIT) programs for mosquitoes. The Sterile Insect Technique against Aedes and Anopheles mosquitoes is actively being researched and developed by the Insect Pest Control Section of the Joint FAO/IAEA Program, of the United Nations. However, developing mass rearing and sex-separation systems for mosquitoes are major technical challenges, because most mosquito life stages are fragile to mass manipulation. Using the SIT against mosquitoes is likely to be most practical where the area intended for control is relatively limited because of the logistical challenges of producing and releasing the large numbers of sterile males that are required.
Is there a possibility that a gene drive placed in the genome of one species could move to the genome of another species?
If two species are sufficiently closely related to support successful hybridization (mating and production of viable offspring) and the species co-occur in the same environment then a gene drive system designed for and introduced into one species could get into the other species through hybridization. For example, this might be expected for sibling species within the Anopheles gambiae species complex, where most of the species are malaria vectors.
The possibility that a gene drive construct could enter and be functional in unrelated species, for example by phenomenon referred to by geneticists as horizontal gene transfer, is highly unlikely based on the current scientific understanding of the frequency of this phenomenon. Furthermore, functioning of engineered gene drive technologies depends upon all elements of the gene drive system operating in very specific cells at very specific times. This specificity requires custom molecular elements that are unlikely to function properly in other species (see Gene Drive Basics).
Is there more than one kind of gene drive?
Yes. There are several mechanisms found in nature by which the preferential inheritance that characterizes ‘gene drive’ can be achieved. Furthermore, different biotechnological approaches can be used to replicate each of these mechanisms.
The type of gene drive that has received the most attention is described as “self-sustaining,” in which the heritable modification is intended to become stably established within interbreeding populations of the target species. There is a growing interest in “self-limiting” forms of gene drive, in which the modification is expected to disappear from the population after some period of time in the absence of repeated releases of the gene drive-modified organism. Researchers are also working on ways to make localizing gene drives, which would limit the spatial spread of the modification within the target population.
Different types of gene drive technologies also have different uses. Uses that aim to reduce the population size of the target species rely on population suppression (or reduction) drives. Uses that aim change some functional or behavioral characteristic of the target species, such as the capacity to transmit a pathogen, rely on population replacement (or modification, alteration or conversion) drives
What are the arguments against development and use of gene drive technologies?
A succinct statement of the arguments against the development and use of gene drive technologies comes from a letter (https://www.geneconvenevi.org/articles/the-case-for-a-global-moratorium-on-genetically-engineered-gene-drives/) signed by 167 civil society organizations calling on the 13th Conference of the Parties to the Convention on Biological Diversity in 2016 to adopt a moratorium on gene drive research and development.
That letter states their concern for the “significant ecological, cultural and societal threats posed by genetically-engineered gene drives, including threats to biodiversity, national sovereignty, peace and food security”.
What are the most common concerns about gene drive modified mosquitoes and their possible use to control malaria?
Several studies have been conducted to identify the harms people are most concerned about for a self-sustaining gene drive technology that might be used to control malaria in Africa. These have identified the potential for harm to human and animal health, biodiversity and water quality as the uppermost concerns. Concerns about stability and predictability of the effect, for example including potential effect on organisms other than the target mosquito population, have been raised. Other technical issues are development of resistance over time on the part of either the mosquito or the pathogen, and the loss of immunity by people in treated areas over time, although these concerns also are valid for other malaria control tools (drugs and insecticides) as well. For each of these concerns, risk analysis must be performed on a case-by-case basis for a specific version of gene drive modified mosquitoes to be used in a particular place under particular conditions to understand and make a decision on whether to move forward with testing or implementation. In addition to technical issues, concerns about governance also have been voiced, including how to ensure affected communities and other interested stakeholders have a voice in decision-making.
(Ref: Roberts et al. 2017 Am J Trop Med Hyg 96:530-33; Teem et al. 2019 Malar J 18:347; Also see Opposing Perspectives below).
What are the possible uses of gene drive-modified mosquitoes?
Those performing research on gene drive technologies in mosquitoes envision several possible uses, such as: 1) preventing transmission of malaria in Africa and other high incidence areas; 2) preventing transmission of arboviruses such as dengue or Zika in regions where they are prevalent; 3) controling transmission of avian malaria that is threatening fragile native bird populations in island habitats.
What are the potential benefits associated with using gene drive technologies as public health tools?
Gene drive technologies will potentially reduce the incidence of mosquito-borne diseases such as malaria in Africa and dengue fever in many parts of the world, resulting in healthier populations. For example, computer simulation modelling predicts that self-sustaining gene drive technologies could be a transformative tool for eliminating malaria in Africa.
In addition to direct public health benefits that might be gained through the use of gene drive technologies, those adopting the technologies could benefit from the technologies’ expected ease of delivery and low cost, which will contribute to sustainability of their protective effects.
What can genetically modified mosquitoes do that more conventional vector control cannot?
Conventional vector control has proven successful in reducing and in some cases eliminating vector-borne diseases. Environmental engineering (e.g., draining swamps) and insecticides (principally DDT) were important in eliminating malaria from North America and Western Europe. In Africa, insecticide-treated bed nets and indoor spraying of insecticides have substantially reduced the burden of malaria. However, insecticide-based control methods are costly, apt to miss important populations of both malaria and dengue-transmitting mosquitoes and are becoming increasingly less effective because of the growing prevalence of insecticide resistance among mosquitoes.
Theoretical advantages of genetically modified mosquitoes are:
- Only the target species is affected directly, unlike the case with some insecticide-based methods.
- They provide protection that benefits all people in the treated area regardless of socioeconomic status or access to healthcare facilities, and do not impose additional burdens or require people to modify their behaviors.
- They can target mosquito populations and breeding sites that traditionally have been the hardest and most expensive to reach using conventional vector control strategies, by exploiting the natural seeking behavior of the mosquitoes to find each other and breeding sites.
- They are well suited to application in both urban and rural environments, and are effective when the vector is present at high or low density.
- They can provide ongoing protection in situations where delivery of other malaria control tools has been disrupted.
Some gene drive technologies could be highly sustainable, requiring only a few releases of gene drive-containing mosquitoes to make large and lasting impacts on a target species. Some gene drive technologies could spread over large geographic areas that are challenging to cover using conventional technologies such as insecticides. These characteristics are expected to make their use highly cost effective. Moreover, ongoing protection provided by mosquitoes carrying self-sustaining gene drive could prevent re-introduction of a disease in regions where it has been eliminated , or protect regions from introduction of new mosquito-borne diseases.
What concerns have been voiced about the use of gene drive modified organisms?
Some voice concerns about the adequacy of current governance mechanisms to deal with issues of transboundary movement. For release of genetically modified organisms that will spread beyond the initial release site, there are questions about from whom prior consent should be obtained. Some stakeholders are concerned that the effects will be unpredictable and that risk assessment methods will not be able to estimate the potential long-term effects to the environment. Some express concerns about the potential extinction of species.
(Ref: Lim and Lim 2019 https://www.twn.my/title2/books/Gene-drives.htm; Critical Scientists Switzerland, European Network of Scientists for Social and Environmental Responsibility, Federation of German Scientists 2020 https://genedrives.ch/wp-content/uploads/2019/10/Gene-Drives-Book-WEB.pdf; ETC Group 2018 https://www.etcgroup.org/sites/www.etcgroup.org/files/files/etc_hbf_forcing_the_farm_web.pdf).
What does it mean when someone says a gene drive will ‘spread’?
The preferential inheritance that characterizes gene drive will result in the frequency or prevalence of the gene exhibiting gene drive to increase within the population of organisms into which it has been introduced. Depending on the characteristics of the gene drive, virtually all of the members of an interbreeding population may eventually contain the modification. The spreading of the gene drive from its initial source of introduction is not unlike the ripple created when a drop of water hits a calm puddle.
What does the GeneConvene Virtual Institute do?
The GeneConvene Virtual Institute aggregates, curates and shares knowledge to advance understanding of genetic biocontrol technologies, such as gene drive, as well as selfish genetic elements found throughout nature.
What is a precautionary approach?
The precautionary principle is based on a statement from the Rio Declaration on Environment and Development, which states “In order to protect the environment, the precautionary approach shall be widely applied by States according to their capabilities. Where there are threats of serious or irreversible damage, lack of full scientific certainty shall not be used as a reason for postponing cost-effective measures to prevent environmental degradation.” The Preamble to the Convention on Biological Diversity also states, “Where there is a threat of significant reduction or loss of biological diversity, lack of full scientific certainty should not be used as a reason for postponing measures to avoid or minimize such a threat.” The precautionary principle is widely often interpreted to mean that if there is uncertainty whether a new technology may cause harm to the environment, it should not be introduced. Therefore, while the principle of precaution as written refers to affirmative action to prevent damage to biodiversity, in the case of GMOs (LMOs), it has been applied to prevent actions that have the potential to harm biodiversity if uncertainty about safety remains.
(Ref: Rio Declaration Principle 15 1992 https://www.un.org/en/development/desa/population/migration/generalassembly/docs/globalcompact/A_CONF.151_26_Vol.I_Declaration.pdf; Convention on Biological Diversity Precautionary Approach https://www.cbd.int/marine/precautionary.shtml).
What is the role of the GeneConvene Global Collaborative?
The Foundation for the National Institutes of Health has been at the forefront of discussions on responsible use of gene drive for public health since 2005. The role of the GeneConvene Global Collaborative is to advance the safe, ethical and rigorous exploration of gene drive technologies by anticipating emerging issues and building consensus for best practices and guidance. The GeneConvene Global Collaborative also serves as a technical resource hub for stakeholders around the world, offering accurate information, support and advice for researchers, decision-makers and funders.
The GeneConvene Global Collaborative operates under the premise that the most constructive approach for exploring the promise of gene drive and other genetic biocontrol technologies is to identify the challenges and, through collaboration, creativity and responsible research, develop mechanisms to overcome those challenges.
What makes a gene drive specific for the targeted species?
Genetic biocontrol strategies can be very species-specific, and this is a feature that makes them attractive for some applications. Much of this specificity rests on the species-specific mating behavior observed widely in nature. Gene drive systems depend on production of viable offspring for their transmission to the next generation. However, some closely related species can and do interbreed and produce viable offspring, and additional measures would need to be taken to limit the technology to only the target species in such circumstances. These measures include constructing the system using components that only function in a particular species. An analogy might be producing an appliance with a plug that only fits electrical outlets in certain countries.
On a more technical level, target species specificity can be determined at multiple levels. First, all engineered gene drives are assemblages of genes and associated regulatory elements needed for the gene drive system to function in the right cells and at the right time in the target organism. Because of the very strict temporal and spatial gene expression requirements for functional gene drives, the regulatory DNA elements used to control gene expression are usually highly species specific. Second, engineered gene drive systems using a Cas enzyme from a CRISPR/Cas system include a “guide” component that recognizes a specific sequence in the DNA of the target species and can be chosen by the researcher for its species uniqueness. Third, in addition to the Cas enzyme acting on the correct sequence, the hundreds of bases of DNA flanking the site on the chromosome cut by Cas also need to be sufficiently specific to the intended target gene in order to achieve ‘drive’. How effective these measures are in achieving species specificity might be evaluated experimentally.
What organizations oppose the development and use of gene drive technologies?
A number of civil society organizations have expressed concerns or outright opposition to the use of gene drive technologies and in some case even the scientific study of gene drive in the laboratory. Many of these have also been opposed to other applications of genetic engineering.
In 2016 at the 13th Conference of the Parties to the Convention on Biological Diversity, there was a call for a moratorium on all gene drive research and development. The organizations that were signatories of that letter and their rational can be found here: https://www.geneconvenevi.org/articles/the-case-for-a-global-moratorium-on-genetically-engineered-gene-drives/. A second call for a global moratorium was issued in 2020: https://www.saveourseeds.org/fileadmin/files/SOS/gene_drive/20200114_NGO_letter_to_all_MEPs_Call_to_support_amendments_on_gene_drive_organisms_in_EP_motion_for_a_resolution_on_COP_15_CBD.pdf.
What other oversight mechanisms will be involved?
The first level of review of plans and protocols for research and testing of genetically modified mosquitoes is likely to be performed by oversight bodies housed at the involved research institutions. Institutional Biosafety Committees may draft institutional biosafety policies and procedures and review individual research proposals for protection of health and the environment. Institutional ethics committees (IECs), also known as institutional review boards (IRBs) or ethical review boards, provide oversight for biomedical and behavioural research involving humans with the aim of protecting the rights and welfare of research participants. Government regulation of gene drive modified mosquitoes may involve more than one regulatory authority, and more than one type of permit for importation and research. Because mosquitoes are mobile, transboundary issues are relevant for gene drive modified mosquitoes and there are many multinational agreements that address transboundary movement. The general consensus of such international conventions is that prior to release into the environment there should be a notification and a bilateral or multilateral consultative process with countries to which the modified organism may move. Mechanisms to support regional harmonization of regulatory requirements for vector control methods in Africa are under development.
(WHO 2014 Guidance Framework for testing genetically modified mosquitoes https://www.who.int/tdr/publications/year/2014/guide-fmrk-gm-mosquit/en/)
What types of risk assessments are appropriate for gene drive-modified mosquitoes?
Risk assessment will take place at many different points in the development pathway. Developers of a technology should make every effort to conduct a thorough risk assessment before each new testing phase or expansion of releases, with the aim of creating the best possible product. In this regard, it has been recommended that an external risk assessment be commissioned before the initial release, to be conducted by external experts with no vested interest in the success of the product, and that this external risk assessment should be made public to help build public confidence in the transparency of the research. This should consider all possible pathways to harm, including both technical and socioeconomic aspects. Communication with potentially affected communities prior to and during the risk assessment process will help with framing the scope of the risk assessment. The results of these risk assessments will help developers understand what data they need to collect, and management plans they need to put in place to reduce any risks to an acceptable level. This information will be helpful in preparing applications to regulatory authorities.
For regulators, the types of risks that are considered are circumscribed by the legal mandates and authorities granted to the agencies charged with the risk assessment (see below). The scope of risks for these agencies are defined by national policies, laws, or regulations. Therefore, the scope of the risk analysis for regulators is not open-ended, and is also under legally prescribed timeframes for completion. The input of citizens/communities are taken into consideration during the specific public consultation phase of decision-making. If their input identifies scientific issues that were missed in the risk assessment, that input might trigger a reconsideration of the risk assessment.
(Ref: CBD Secretariat 2000 Cartagena Protocol on Biosafety to the Convention on Biological Diversity, Annex III https://bch.cbd.int/protocol/text/;;US Environmental Protection Agency 2020 Ecological Risk Assessment. https://www.epa.gov/risk/ecological-risk-assessment);
When might it make sense to use genetic biocontrol?
There are a number of circumstances in which genetic biocontrol approaches might be useful. For example, when other control strategies are or are becoming ineffective, as is the case for control of the human malaria vector in sub-Saharan Africa. Insecticide-based strategies have contributed more to averting cases of malaria than any other intervention, but it is well documented that those strategies are fragile and, in some cases, failing, largely due to the mosquito vectors becoming resistant to all commonly used insecticides. Genetic biocontrol strategies can be a powerful adjunct to insecticide-based strategies. The living biocontrol organisms can seek out breeding sites of the target species that are difficult to reach with insecticides. Use of genetic biocontrol may also reduce dependence upon insecticides, slowing development of insecticide resistance and extending the utility of some useful insecticides.
Where is genetic biocontrol currently being implemented?
The genetic biocontrol known as the Sterile Insect Technique has been used safely across the globe for decades to control agricultural pests. For example, in Central America sterile New World Screwworm flies are released to prevent the northern migration of these harmful livestock pests from South America into Mexico, Central America and the Southern US. Mass reared sterile male Mediterranean Fruit Flies are or have been used to control this major pest of citrus and other fruits in Argentina, Mexico, Portugal, Dominican Republic, Guatemala, Spain and the USA. Sterile male Tsetse flies have been used to control these important vectors of African sleeping sickness.
In the United States, for example, the Mediterranean Fruit Fly Preventive Release Program (Medfly PRP) in Los Alimitos, California uses the Sterile Insect Technique to prevent establishment of Mediterranean Fruit Flies colonies in California. The eradication of the pink bollworm, a invasive and destructive species, from the US in 2018 came after decades of effort that included among other things the use of the Sterile Insect Technique.
Who are developing gene drive technologies?
Gene drive technologies are being researched and developed mainly in academic institutions as evidenced from published scientific research. Currently there is no published evidence that multinational companies are involved in or have interests in gene drive technologies, especially those that are self-sustaining.
Who decides whether gene drive technologies are safe and effective?
For gene drive-modified mosquitoes intended to be used as public health tools, there are many levels of oversight and decision-making. The World Health Organization (WHO) has issued guidance for testing genetically modified mosquitoes, including those carrying gene drive modifications, describing considerations for safety and efficacy testing at every stage of development and implementation. If developers ultimately wish to obtain WHO recommendation for their technology as a public health tool, they will need to work through WHO processes for evaluation of the safety and efficacy of vector control products. The decision of whether to utilize these technologies within national disease control programs will be made by government authorities.
Proposed research must be reviewed and approved by biosafety and ethics committees at the institutions where the research is conducted and/or at regional or national levels before it is allowed to commence. National regulatory authorities also must be consulted regarding safety of research involving human research participants or use of genetically modified organisms. Importantly, researchers must consult with the communities hosting any field research, to determine whether their research plans are acceptable to community members.
Who determines what is included in the knowledge base of the Virtual Institute?
The GeneConvene Virtual Institute‘s Administrator, using the Institute’s content inclusion/exclusion guidelines makes decisions regarding content. The GeneConvene Virtual Institute strives to be an inclusive, balanced, fair and transparent source of knowledge about gene drive and other genetic biocontrol technologies. To achieve the breadth and depth necessary to capture the broad range of activities in the gene drive domain the GeneConvene Virtual Institute does not vet the content entering the knowledgebase for accuracy.
Who is funding current research and development of gene drive technologies?
National governments and not-for-profit foundations are currently the main funders of gene drive research. The Bill & Melinda Gates Foundation funds a number of gene drive-related projects internationally, including the GeneConvene Virtual Institute. The Gates Foundation requires its grantees to agree to global access requirements that guarantee any products resulting from the research will be made accessible to people. In the United States the National Institutes of Health and the Defense Advanced Research Projects Agency fund research in this and related areas. The Open Philanthropy Project also has funded work on this topic.
A more comprehensive and critical review of gene drive funding can be found in chapter 3, pp 161-164 of this 2020 report from Critical Scientists Switzerland (CSS), European Network of Scientists for Social and Environmental Responsibility (ENSSER) and Vereinigung Deutscher Wissenschaftler (VDW)
Who will determine if gene drive technologies will be used?
While gene drive-engineered organisms might hold promise in addressing certain specific needs, they may never be used for any number of reasons. For example, regulators may decide not to approve a field test or policy-makers or communities may not accept the technology. It is important that stakeholders have timely and accurate information on which to base these decisions.
For gene drive-modified mosquitoes intended to be used as public health tools, there will be many levels of oversight and decision-making. The World Health Organization (WHO) has issued guidance for testing genetically modified mosquitoes, including those carrying gene drive modifications, describing considerations for safety and efficacy testing at every stage of development and implementation. Approval must be obtained from biosafety and ethics committees at the institutions where the research is conducted (or equivalent national committees). National regulatory authorities must review and approve applications to import and test gene drive-modified mosquitoes before research can proceed. Communities where testing is proposed must be consulted on the acceptability of research plans. If developers wish their technologies to be eligible for recommendation by WHO, plans for and results of field trials also must be reviewed through their mechanisms for evaluating new vector control tools.
Why are mosquitoes good candidates for gene drive technologies?
One of the earliest contemplated uses of gene drive systems was to combat mosquito-borne diseases such as malaria and dengue fever, which cause death and disability in many parts of the world. Gene drive systems work best in organisms with short generation time that reproduce sexually and have many offspring. Therefore, mosquitoes are a great candidate for gene drive approaches. An active and efficient gene drive in these insects might be expected to spread through populations on a relatively short time scale (years).
What are the next steps for gene drive in public health?
Many technical, safety and policy questions remain to be addressed to ensure that gene drive technologies continue to be explored effectively, responsibly and ethically. Among other issues, gene drive-engineered organisms have the potential to cross national borders, raising the need for mechanisms for regional coordination of regulatory and policy requirements. Additional thought must be given to expectations for safety and efficacy that would justify moving to field testing. Consensus must be achieved regarding appropriate mechanisms for authorization of releases, including community consultation. In all areas, coordination across potential applications and sectors is critical to safely unlock the potential of gene drive to address malaria and other public health needs.
Why is gene drive research being funded by the US Department of Defense?
The Safe Genes program funded by the Defense Advanced Research Projects Agency was established with the goal of improving the biosafety of gene editing and gene drive tools and protecting against their irresponsible or malign use, by developing methods to restrict or reverse the propagation of engineered genetic constructs.
(Ref: Defense Advanced Research Projects Agency https://www.darpa.mil/news-events/2016-09-07)
Why might gene drive be used instead of other genetic biocontrol techniques?
There are at least three reasons why gene drive systems might be used in lieu of other genetic biocontrol techniques.
First, they are better suited for control needs that extend over large areas (country level) because gene drive technologies have the potential to persist and spread within and between populations of the target organism. This should make them easier to deliver and more effective than current genetic biocontrol technologies.
Second, genetic biocontrol methods such as the Sterile Insect Technique and related techniques require continuous rearing and release of large numbers of insects to sustain control of the target organism. Maintaining such programs over time can be challenging and resource intensive. The persistence characteristics of gene drive technologies could contribute to their sustained impact over time and space, a feature that may be well suited in cases where resources for pest control are very limited.
Third, gene drive technologies can be designed either to reduce or eliminate the target organism from the local environment or to leave the target species in the environment but to alter it genetically in such a way that it is no longer a threat. This is a relatively unique feature of gene drive technologies.
Why must the risk of gene drive technologies be assessed on a case-by-case basis?
Without knowing the characteristics of a particular intervention involving the use of gene drive technologies and the environment where it will be used, it is not possible to identify specific relevant hazards and the magnitude of harms that could result from those hazards. Without an understanding of the specific use-case, concerns tend to be generalized and somewhat speculative.
Why not just invest additional resources into more effectively applying current existing control strategies to eradicate these diseases?
Although insecticide-based tools can be very effective against malaria, they are extremely costly to maintain, and it is widely recognized that current tools will be insufficient to eradicate the disease. Insecticide-based tools have been less effective against mosquito vectors of arboviral diseases, where environmental management may play a more important role. Insecticide resistance is a problem in the mosquitoes that transmit both malaria and common arboviral diseases. Even if disease elimination from some endemic areas was feasible with current control measures, there is the possibility that resident vector-competent mosquito populations can permit reintroduction of the disease from other areas where the disease is not yet effectively controlled, especially when government control breaks down because of political instability or countries do not have the resources to employ or sustain their control programs.
(Ref: Feachem et al. 2019 Lancet 394:1056 https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(19)31139-0.pdf; Dengue Virus Net http://www.denguevirusnet.com/mosquito-control.html).
Why not use Sterile Insect Technique programs to eliminate malaria in Africa?
Malaria in Africa is found from northern South Africa to the southern edge of the Sahara Desert, an enormous area. The Sterile Insect Technique and related genetic biocontrol programs require considerable infrastructure in order to continuously rear and release large numbers of insects to sustain control of the target insect. While it is quite possible or even likely that these programs could contribute to malaria elimination in relatively limited urban areas, they are much less suited to deal with malaria throughout the abundant remote and highly dispersed towns and villages across the continent. It is the persistence and spread of gene drive technologies within and through specific malaria-transmitting mosquito species that is expected to enable the technology to impact malaria transmission over wide areas with highly dispersed human populations. Malaria elimination from Africa has involved and will continue to involve the use of many tools. Gene drive technologies hold promise to provide a new and highly effective set of tools that can contribute to malaria elimination.
Why not use the self-sustaining Wolbachia approach developed by the World Mosquito Program to eliminate malaria in Africa?
The World Mosquito Program developed a unique strain of Aedes aegypti that is infected with the intracellular bacteria Wolbachia and the infection is transmitted from parent to progeny. These bacteria-infected mosquitoes are immune to infection by dengue, yellow fever and Zika viruses, Releasing Wolbachia infected mosquitoes results in the spread of the bacteria through populations of Aedes aegypti, rendering them unable to vector human pathogenic virusea. This method is showing promise for controlling these viral infections in urban areas. Strains of African human malaria-transmitting mosquitoes (Anopheles species) analogous to the Aedes aegypti produced by the World Mosquito Program do not exist, and currently there is no evidence that Wolbachia protects against the parasites that cause human malaria. There is more research to be done before it is known whether a protective strain of Anopheles can be produced. Perhaps more importantly, there are technical differences between gene drive technologies and Wolbachia-based technologies that would require larger numbers of Wolbachia-infected mosquitoes to be released repeatedly. This might present operational and logistic limitations that would limit the use of Wolbachia-based technologies against malaria across Africa.
Will gene drive technologies be highly profitable to those developing them?
Self-sustaining gene drive technologies are being designed as long-term, durable, and low-cost solutions requiring few additional inputs following the release of organisms containing the technology. A product that is highly species specific, will not need to be reapplied, and is intended to provide long-lasting effectiveness presents challenges when looking for a profitable business model.
Self-limiting gene drive products and other genetic biocontrol technologies are likely to require regular applications of the technology over space and time in order to maintain their intended effects. These types of products may have more attractive characteristics for business enterprises.
Will it be necessary to stop other forms of vector control in order to get gene drive modified mosquitoes to establish in the population?
Gene drive modified mosquitoes are being developed as complementary tools in the context of integrated vector management programs. Reductions in the density of the target population due to bed nets, spraying, etc., will actually help the establishment of gene drive-modified mosquitoes. When the natural mosquito population has been diminished by standard control methods, fewer modified mosquitoes will have to be released to achieve establishment. The only issue is that insecticide treatments should not be performed immediately after releases of modified mosquitoes. Once gene drive modified mosquito strategies are in place, it is anticipated that these regions will become less dependent upon insecticide-based control, and this lowered exposure should help to prevent the development of insecticide resistance. There will be long-term synergy between the different methods, not interference.
Will locally eliminating a mosquito species have unintended harmful effects on the local ecology?
There are over 3000 species of mosquito in environments ranging from the arctic to the most southern regions of the world outside of Antarctica. So, it is not possible to presume that there is one answer to this question. For gene drive technologies applied to the human malaria-transmitting mosquito, Anopheles gambiae, there are several important considerations. These mosquitoes are confined solely to the African continent. Anopheles gambiae is one of approximately 800 species of mosquito in Africa, and ecological research and experience from long standing efforts to reduce and remove the species from environments supports the conclusion that it is not a “keystone species”. A keystone species is defined by ecologists as a species upon which an ecosystem greatly depends and whose removal will trigger a drastic change in that ecosystem.
(Ref: Collins et al., Med Vet Entomol. 2019 33:1 https://pubmed.ncbi.nlm.nih.gov/30044507/; Bohmann et al.,PLoS One. 2011; 6:e21441 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0021441; WHO https://www.who.int/news-room/fact-sheets/detail/malaria.
Will the use of gene drive modified mosquitoes cause people currently employed in vector control programs to lose their jobs?
: Implementation of genetically modified mosquito technologies will involve preparatory analysis, site-specific product development, application/delivery, and post-implementation monitoring and evaluation work. Since gene drive-modified mosquito technologies are intended to be used in integrated vector management programs, many of these activities may be incorporated into ongoing disease control plans, and national vector and disease control programs are anticipated to play a central role. So, gene drive mosquito technologies are not expected to displace workers in the vector control sector.