What hazards are associated with gene drives?
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This question must be addressed for each proposed use of gene drive technology individually. The safety of gene drive technologies is an important concern shared by all stakeholders. Expert sources such as the Convention on Biological Diversity and the World Health Organization have agreed that because of the diversity of possible applications of gene drive their safety must be evaluated on a case-by-case basis. 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 there are any risks associated with the products of gene drive technology, and if so, whether they are acceptable.
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No. Gene drive occurs frequently in nature irrespective of 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 (sleeping sickness). What is newer is our ability to mimic natural drive systems using techniques of molecular biology.
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Most expressed concerns fall into a few major categories:
- Transboundary movement: Questions have been raised about the adequacy of current governance mechanisms to deal with the implications of movement of gene drive-modified organisms across national boundaries.
- Consent: For release of gene drive-modified organisms that will spread beyond the initial release site, there are questions about from whom prior consent should be obtained, as well as appropriate mechanisms for obtaining that consent.
- Environmental effects: Some stakeholders are concerned that the effects of gene drive-modified organisms will be unpredictable and that risk assessment methods will not be able to estimate the potential long-term effects to the environment.
- Extinctions: Some express concerns about the population suppression technologies might result in eradication of the target species.
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Is the potential for autonomous transboundary movement by certain types of gene drive-modified mosquitoes unprecedented?
No. There are established precedents for autonomous transboundary movement. Classical biological control, for example 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. The International Plant Protection Convention has created guidelines for the export, shipment, import and release of biological control agents that describe the responsibilities of governments and importers. 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. And the possibility for autonomous dispersal, for example of pollen or spores, also has been a consideration for GM crops.
Have potential harms caused by possible use of gene drive-modified mosquitoes to control malaria in Africa been considered?
Yes. Several studies have been conducted to identify the potential harms to recognized protection goals that people are most concerned about. For a self-sustaining gene drive technology that might be used to control malaria in Africa, these studies have identified the potential for harm to human and animal health, biodiversity, and water quality as the uppermost concerns.
In theorizing about possible pathways to these harms, questions about stability of the trait over subsequent generations and predictability of the effects, for example including potential effect on organisms other than the target mosquito population, have been raised. Other technical issues include possible 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 same concerns also are pertinent for other malaria control tools (drugs and insecticides). WHO has recommended that risk analysis must be performed on a case-by-case basis for each specific version of gene drive-modified mosquitoes to be used under particular conditions to help stakeholders understand and make a decision on whether to move forward with testing or implementation.
For more information (Also see FAQs on How to manage risks):
Highly unlikely. This is extraordinarily improbable because it would require a series of highly unlikely events to occur:
- DNA transfer: analyses of the genomes of primates (including humans) have not revealed the presence of any insect genes, suggesting that a transfer of genes from mosquitoes to humans (horizontal gene transfer) has never been detected.
- DNA location: it would also be highly unlikely that even if mosquito DNA were transferred when the mosquito bites, that DNA could make its way inside in a human cell, and even less likely that it would make its way to a human sperm or egg cell in a way that retains its function.
- DNA functionality: most gene drive systems are created so that the gene drive will only be active in the reproductive system of the mosquito, which means the molecular components comprising the gene drive are not likely to function within a human cell.
Given that each event individually has an extremely low probability of occurring, taken together the probability of a functional gene drive being transferred from a modified mosquito to a human is expected to be exceedingly low. Nonetheless, this question must be addressed in case-by-case risk assessment.
Gene drive mosquitoes are not intended to cause extinction of the mosquito species in which they are being used. Mosquito species extinction is not necessary for gene drive technologies to have the desired public health effect.
Although one type of genetically modified mosquito technology is intended to suppress populations of the targeted mosquito species by reducing its reproductive rate, the goal is to reduce or eliminate disease transmission, not the mosquito. This can be done by reducing the numbers of the target mosquito species to a level too low to maintain the life cycle of the pathogen, but not so low that it causes species extinction.
Yes, in theory. Self-limiting gene drive systems are designed specifically to disappear from the population after some period of time in the absence of repeated releases of the gene drive-modified mosquitoes. Self-sustaining gene drive-modified mosquitoes (mosquitoes that contain a heritable modification that is intended to become stably established within interbreeding populations) theoretically could be controlled or eliminated by any of several strategies following their release into the environment. Possible ways to eliminate gene drive modified-mosquitoes from the environment include the following:
- Using chemical insecticides
- Releasing large numbers of mosquitoes carrying natural or engineered DNA sequences that are resistant to the gene drive
- Disabling or removing the initial gene drive by releasing a second gene drive technology specifically designed to target and inactivate the first technology
- Using small molecules that specifically inhibit the gene editing enzyme Cas (if part of the gene drive system), thereby shutting off the gene drive
Some of these strategies have been tested in the laboratory or insectary, but they have not been tested in the field since no field testing of gene drive-modified mosquitoes has yet been conducted.
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There are over 3000 species of mosquito in environments ranging from the arctic to the most southern regions of the world outside of Antarctica, and approximately 800 species of mosquito have been observed in Africa. So, it is not possible to presume that there is one single answer to this question. Vector management has always been a mainstay of efforts to control malaria and other mosquito-borne diseases. 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. The Anopheles gambiae complex is made up of eight sibling species, of which Anopheles gambiae s.s. is one, so these make up only a small percentage of the entire African mosquito population. Ecological research on the behavior of mosquitoes and experience from long standing efforts to reduce and remove the species from environments supports the conclusion that Anopheles gambiae 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.
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No. Mosquitoes obtain sugar as a source of energy from a variety of different sources, including flowers. In visiting flowers, they may occasionally pick up and transmit pollen. However, in tropical or subtropical regions of the world these flowers will also be visited by many other insect species, including those better adapted for pollination than mosquitoes. There is no experimental or circumstantial evidence that Anopheles or Aedes mosquitoes are important pollinators in Africa, making it extremely unlikely that elimination of these mosquitoes would have negative effect on local plant communities.
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Is it possible that elimination of one mosquito species could lead to an increase in other mosquito species in the area?
Yes. The issue of competitive replacement, also called niche replacement, is a possibility that the World Health Organization and others have recommended should be considered in risk assessment. There are two parts to the question of whether this could lead to harm, however. The first part of the question is whether it might happen. The second part is whether it would result in increased disease transmission. For example, there is evidence for competitive replacement of Aedes aegypti with Aedes albopictus, where they have overlapping distribution. But Aedes albopictus is widely thought to be less competent than Aedes aegypti for transmitting arboviruses such as dengue so it is unlikely that this would result in substantially greater disease risk overall. An extensive study of the effects of insecticide-based vector control programs targeting Anopheles species in Africa suggests that reduction in numbers of Anopheles gambiae mosquitoes was sometimes followed by a local increase in other related species, but these other species were less efficient vectors of malaria transmission.
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Is there a possibility that a gene drive system placed in the genome of one species could move to the genome of another species?
Yes, genes can move between species under some conditions, although that does not mean that they will be functional in the new species.
DNA moves between species by two routes: 1) interspecific hybridization (introgression) and 2) horizontal (or lateral) gene transfer. If two species are sufficiently closely related to support successful hybridization (mating and production of viable and fertile offspring) and the species co-occur in the same environment, then a gene drive system designed for and introduced into one species could move into the other species. For example, this might be expected for sibling species within the Anopheles gambiae species complex, where most of the species are malaria vectors.
Horizontal (lateral) gene transfer refers to the movement of DNA between species that does not involve mating or hybridization. Horizontal gene transfer is common among bacteria but rare among plants and animals, where it happens on an evolutionary time scale through the mechanisms that remain unclear. Rarer still are examples where the DNA transferred is expressed and retains its original function.
The possibility that an engineered gene drive construct could enter and be functional in unrelated species appears highly unlikely based on the current scientific understanding. 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 will not function properly in other species. Nevertheless, this question should be considered in case-by-case risk assessment.
For an engineered gene drive to function, a small number of genes contained within the gene drive element need to be expressed in the right cells and at the right time within the target organism. The genetic switches that turn those important genes on and off at the right time will not function in all species, particularly species distantly related to the original host species. So not only will the gene drive need to get into the right cells (germline cells) of a second organism 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.
What safety characteristics of gene drive and other genetically modified mosquitoes have been recommended for testing?
Phased testing will include examination of safety as well as efficacy characteristics. As recommended by the World Health Organization and the Convention on Biological Diversity, this would involve examination of possible adverse effects on human or animal health or the environment, including protection of biodiversity. Health hazards that have been identified as priorities for consideration include: the potential for the modification to cause increased abundance of mosquito species that carry the pathogen of interest; alteration that would result in an increased ability of mosquitoes to transmit the targeted pathogen or other pathogens; alterations that would reduce the ability to control the mosquitoes with conventional methods; increased allergenicity or toxicity of mosquitoes for humans or other organisms; or increased virulence of pathogens carried by the mosquito. Environmental hazards that have been identified as priorities include the potential for: spread of the modification to other species that would cause harm to the ecosystem; indirect harm to other species that depend on the modified mosquitoes for some essential service; increase in a harmful competitor species; or harmful higher order effects to the ecological community.
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Yes, depending upon the type of gene drive and extent of release. Insecticide resistance is not required for gene drive-modified mosquitoes to function successfully. Care is being taken not to introduce modifications that might increase insecticide resistance in the local mosquito population. For example, the gene drive construct can be introgressed into the genetic background of the local target species so that their other characteristics remain unchanged. Addittional methods for controlling gene drive-modified mosquitoes, including genetic mechanisms and small molecule approaches, also are being explored.
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This is a question that will be addressed in risk assessment (see How to manage risks?). Risk assessment will take into account what other diseases that can be transmitted by the target mosquito species are present in the region where the gene drive-modified mosquitoes will be released. If necessary to support risk assessment, experiments can be conducted in the laboratory to measure the ability of the gene drive-modified mosquitoes to transmit different pathogens. Such experiments involve artificial feeding on blood containing the pathogen, using a membrane feeding device, and then examining the ability of the pathogen to grow in the mosquito and/or to be ejected in the mosquito’s saliva as might happen when it bites.
For more information: https://www.youtube.com/watch?v=nfZrSH7uQ08; https://www.who.int/publications/i/item/9789240025233;
We do not yet know the answer to this question as it is dependent upon many variables, including clarification of the regulatory pathway and collection of information needed to support risk assessment for different gene drive systems and in different venues.
What is the difference between genetically modified-mosquitoes and gene drive-modified mosquitoes?
Gene drive-modified mosquitoes are a type of genetically modified-mosquitoes. In both cases, mosquitoes of the targeted species are modified using modern biotechnology to exhibit one or more different traits from wild type (non-modified) mosquitoes of the same species. An example of a desirable new trait would be a decreased ability of the modified mosquitoes to transmit diseases such as malaria or dengue. Modifications might involve altering the sequence of existing genes, disabling or excising of existing genes, or introducing new genes or other genetic elements within the mosquito genome.
When not coupled to a gene drive, a gene (including any introduced genetic modification) is typically transmitted to the progeny from mating of modified with wild type mosquitoes according to the standard (Mendelian) pattern of inheritance, where each gene has a 50% chance of being passed from the parent to the next generation. If the gene or genetic modification is associated with a fitness cost (reduced competitive ability), the related trait is expected to disappear from the population over time. If the fitness cost is severe, the introduced gene(s) can disappear rapidly; this would be the case, for example, if the modification caused reduced fertility in those mosquitoes that carried it.
When coupled with a gene drive, the genetic modification is inherited preferentially. The related new trait will eventually become dominant in the population because more than 50% (sometimes almost 100%) of the progeny from matings between gene drive-modified mosquitoes and their wild-type counterparts inherit the modification.
For more information: https://www.geneconvenevi.org/gene-drive-defined/
No. CRISPR (which stands for Clustered Regularly Interspaced Short Palindromic Repeats) is a family of DNA sequences originally observed in bacteria and derived from viral DNA upon initial infection. It acts as a defense system to protect those bacterial cells during subsequent viral invasions. The CRISPR DNA sequence is transcribed within the bacterial cell to RNA, which works as a sequence specific guide for a CRISPR-associated protein (called a Cas nuclease) that cleaves viral nucleic acid in a region complementary to the CRISPR sequence, disabling the virus. There are a variety of CRISPR/Cas types with different sequence recognition and cleavage abilities.
This CRISPR-Cas system has been adapted for use as a genome altering tool by substituting specifically constructed guide nucleic acid sequences that direct the Cas protein to cut at a particular target sequence in the DNA of an organism. This system has been found to work very efficiently in many types of cells and can be used to add, remove, or alter/edit the sequence in a targeted gene in an organism’s genome. CRISP/Cas based tools are being developed as therapies for several genetic diseases. They are also being used as one method to develop synthetic gene drives.
For more information: https://www.youtube.com/watch?v=UKbrwPL3wXE