The wasp Aleiodes indiscretus is used to control gypsy moth.  They can be reared to large numbers and released in pest-infested areas
Image: Public Domain.

Biocontrol, short for biological control, uses living organisms to reduce and control populations of pest organisms. In classical biological control the pest organisms can be an invasive animal or plant species with no or few natural enemies in its new location, and the biocontrol agent can be 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 also 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.

For more information:

Biocontrol in Australia: Can a carp herpesvirus (CyHV-3) deliver safe and effective ecological restoration?

Biological control of pests and a social model of animal welfare

Biocontrol: what is it?

North American Invasive Species Management Association (NAISMA) is a good place to explore this topic further.

This is a form of biological control in which genetic variants or genetically modified forms of the 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 an agricultural pest species or a vector species that transmits human, animal, or plant diseases. Genetic biocontrol has the advantage of expanding the scope of target pest species beyond those for which classical biocontrol agents are available.

For more information:

See also:

The promise and challenges of genetic biocontrol for malaria elimination https://www.mdpi.com/2414-6366/8/4/201

Most forms of genetic biocontrol have a similar goal as classical biocontrol: to reduce the population of a problem-causing organism, generally by inhibiting its ability to reproduce. These are termed “population suppression strategies.” Some forms of genetic biocontrol are now being developed that aim to modify the pest organism in such a way that its ability to cause the problem is reduced. This might be accomplished, for example, by inhibiting its ability to transmit a disease-causing pathogen. These are termed “population replacement” or “population modification strategies.”

Various types of genetic biocontrol have been proposed for use in public health, agriculture, and conservation. For public health, they can contribute to preventing transmission of vector-borne infectious diseases. For agriculture, they can help to reduce crop loss caused by insect pests. For conservation, they have been proposed as a method for controlling invasive species that cause loss of biodiversity.

For more information:

https://www.youtube.com/playlist?list=PLbopRNGowKJ9dtCMDZ9_LQRHyw084vgIP
https://www.geneticbiocontrol.org/

There are a number of conditions in which genetic biocontrol approaches can be useful. For example, when other control strategies are or are becoming ineffective, as is the case with development of pesticide resistance in insects or weeds. Like classical biocontrol, genetic biocontrol strategies can be a powerful adjunct to pesticide-based strategies and reduce our dependence upon them. Genetic biocontrol can also be useful in situations where conventional chemical approaches cannot fully address the problem because it is so difficult or expensive to deliver these approaches in areas where pests breed or cause damage. Living biocontrol organisms have the advantage of being biologically inclined to seek out the pest they are intended to control, simplifying delivery. Additionally, genetic biocontrol may be considered by some as more environmentally friendly or humane than chemical approaches.

This is a matter of definition. If one defines genetic modification as a change in the genetic material through the use of modern biotechnology (genetic engineering), then the answer is no. Genetic biocontrol does not always use organisms that are genetically modified. The genetic make-up of an organism can be altered in several ways other than via molecular biology. Traditionally, this has been accomplished over time through selective breeding. Genetic changes also can be introduced using irradiation, as is the case for the classical Sterile Insect Technique (SIT), or by infection of the organism with a new microbe, such as a virus or bacterium.

There are variants of SIT and other biocontrol strategies that involve the release of insects that have been modified in the laboratory (genetically engineered) to effect a functional change. Genetic changes introduced using molecular biology technologies are expected to be more controllable and predictable than the random chromosomal damage caused by irradiation.

Fore more information:

https://royalsociety.org/topics-policy/projects/gm-plants/how-does-gm-differ-from-conventional-plant-breeding/

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 ionizing radiation, which causes a multitude of random chromosomal mutations that lead to infertility. Large numbers of irradiated insects are released into wild populations of the same 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 over time can result in a reduction of the target population and in some cases its local elimination.

Another example of genetic biocontrol involves 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.

For more information:

https://www.iaea.org/sites/default/files/19/02/controlling-insect-pests-with-the-sterile-insect-technique.pdf
https://www.youtube.com/playlist?list=PLbopRNGowKJ9dtCMDZ9_LQRHyw084vgIP

The genetic biocontrol known as the Sterile Insect Technique, based on irradiation, 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 important livestock pests from South America into Mexico, Central America, and the Southern US.  Mass reared radiation-sterilized male Mediterranean Fruit Flies are or have been used to control this major pest of citrus and other fruits in countries including Argentina, Mexico, Portugal, Dominican Republic, Guatemala, Spain, South Africa, and the USA.

Genetic engineering also is being applied to control of agricultural pests such as Mediterranean Fruit Fly and Fall Armyworm. Oxitec’s Friendly^TM technology for Fall Armyworm has been approved by the Brazilian biosafety agency.

For more information:

https://www.iaea.org/topics/sterile-insect-technique;

https://www.taylorfrancis.com/books/oa-edit/10.1201/9781003169239/area-wide-integrated-pest-management-jorge-hendrichs-rui-pereira-marc-vreysen; https://www.oxitec.com/en/food-sustainability

Many infectious disease agents are transmitted to humans or animals by blood-feeding insects or ticks, termed disease vectors. Vector-borne diseases pose an enormous public health burden, causing an estimated 700,000 deaths per year worldwide. Mosquitoes are the most important vectors of human disease, transmitting many different parasitic and viral pathogens including those that cause malaria, filariasis, dengue, chikungunya, Zika, and yellow fever.

For more information:
https://www.who.int/news-room/fact-sheets/detail/vector-borne-diseases

Today, control of vector-borne diseases is largely accomplished using drugs to prevent or treat human infection by the disease-causing agent (pathogen) and pesticides to prevent or reduce the vector populations thereby decreasing their transmission of the pathogen. However, pathogens develop resistance to widely used drugs, and vectors develop resistance to frequently used pesticides. Moreover, effective drugs are not available for some pathogens, such as arboviruses. Vaccines are available for some but not all vector-borne diseases. Environmental management, which aims to eliminate potential breeding sites of disease-carrying vectors, also is being used. However, the utility of this measure is limited by the difficulty in finding and removing all possible breeding sites. This situation creates an urgent need to look for new and alternative control measures.

For more information:

https://www.who.int/westernpacific/activities/integrating-vector-management
https://apps.who.int/iris/bitstream/handle/10665/272533/9789241514057-eng.pdf, https://apps.who.int/iris/handle/10665/204588

Mosquitoes can transmit disease causing agents (pathogens) through their bite. Female mosquitoes require nutrients found in blood to support the development of their eggs. Therefore, only female mosquitoes bite humans or other animals to obtain that blood, while male mosquitoes feed exclusively on plants. If the human or animal the female mosquito bites is infected with a suitable level of a pathogen capable of being transmitted by mosquitoes, the female mosquito can pick the pathogen up when she takes a blood meal. She may then be able to pass that pathogen to the next human or animal she bites.

Some pathogens cannot be transmitted by mosquitoes in this way. To be transmitted to the next person, the pathogen must survive the mosquitoes’ digestive system, ideally to multiply and make its way back into the mosquitoes’ mouthparts. Many blood-borne pathogens, like HIV and hepatitis viruses, have not been found to survive in mosquitoes. Moreover, the pathogen and the mosquito must be compatible – only certain pathogens can survive and multiply in certain mosquito species. For example, 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.

Yes, several biological control approaches are being taken against mosquitoes.

• Fish: Among the more conventional biocontrol approaches, fish such as those in the genus Gambusia (aka “mosquitofish”) have been employed for controlling mosquito breeding in water bodies, such as rice cultivation areas, for decades.
• Bacteria: Some isolates of the bacteria Bacillus thuringiensis and Bacillus sphaericus are widely used to control mosquitoes and are sold for use by gardeners and property owners as an alternative to chemical pesticides.
• Fungi: 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.
• Genetic: Genetic biocontrol approaches are also being applied to mosquitoes. Genetic biocontrol methods can be used to reduce the numbers of mosquito vectors or limit their ability to carry one or more pathogens. For example, three versions of the Sterile Insect Technique are being tested in Aedes aegypti, a mosquito responsible for transmitting dengue, yellow fever, Zika and other human pathogenic viruses. These techniques include: classical Sterile Insect Technique employing radiation-induced sterilization to reduce productive mating; Incompatible Insect Technique that exploits certain effects of the intracellular bacterium Wolbachia to prevent productive mating; genetically engineered mosquitoes which contain genes that are lethal to the next generation of mosquitoes. A different type of method, meant to have persistent effects, uses Wolbachia bacteria in a way that permanently immunizes the mosquito Aedes aegypti against infection by dengue, yellow fever, and Zika viruses.

For more information:

https://www.youtube.com/playlist?list=PLbopRNGowKJ9dtCMDZ9_LQRHyw084vgIP
https://www.iaea.org/topics/sterile-insect-technique/mosquitoes

https://www.in2care.org/
https://www.oxitec.com

https://mosquitomate.com/
https://www.worldmosquitoprogram.org/

Vaccines are important tools against many infectious diseases. Several potential dengue vaccines are being studied and one has been recommended for use under limited circumstances. Likewise, research on malaria vaccines has been ongoing for decades and one vaccine has received WHO recommendation for children living in regions of high disease transmission, where it has demonstrated a reduction in severe disease. More recently, another type of vaccine also has been shown in clinical trials to reduce malaria incidence in young children, and this vaccine has been approved for use in certain countries.

Malaria and dengue have proven to be very challenging diseases to control. Successful control and/or elimination will require multiple different tools. Vector control is expected to remain important for several reasons. For example, vaccines that prevent clinical disease do not stop transmission of the parasite or virus, so the threat of infection remains. The need for approved vaccines currently exceeds availability leaving many unprotected. And, vaccines generally need to be administered in multiple doses, raising issues of cost and adherence.  WHO has taken the position that new vector control tools are urgently needed, and that the potential contribution of genetically modified-mosquitoes should continue to be explored.

For more information:

https://www.who.int/news-room/fact-sheets/detail/vector-borne-diseases
https://www.cdc.gov/dengue/prevention/dengue-vaccine.html
https://www.who.int/publications/i/item/dengue-vaccines-who-position-paper-september-2018
https://www.who.int/news/item/06-10-2021-who-recommends-groundbreaking-malaria-vaccine-for-children-at-riskhttps://www.who.int/news/item/14-10-2020-who-takes-a-position-on-genetically-modified-mosquitoes
https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(19)31139-0.pdf

https://www.ox.ac.uk/news/2023-04-13-r21matrix-m-malaria-vaccine-developed-university-oxford-receives-regulatory

Although conventional insecticide-based tools have been a mainstay in fighting insect disease vectors, they have limitations. Insecticide-based tools required continuing reapplication that can be costly to maintain and insecticide resistance is an ongoing problem. Insecticide-based tools historically have been less effective against some mosquito vectors, such as those of arboviral diseases, due to the difficulty of reaching their breeding sites. WHO has taken the position that new tools are urgently needed for vector-borne diseases.

For more information:

https://www.who.int/news-room/fact-sheets/detail/malaria
https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021
https://www.who.int/publications/i/item/9789240015791
https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue
https://www.who.int/news/item/14-10-2020-who-takes-a-position-on-genetically-modified-mosquitoes

Genetic biocontrol can be applied to other disease vectors besides mosquitoes. For example, Sterile Insect Technology has been used to control the tsetse fly vector of African trypanosomiasis (sleeping sickness). Some researchers also are studying the applicability of genetic biocontrol to ticks.

Some human and animal diseases, such as Lyme disease and plague, are transmitted directly or indirectly by rodents. For these, the same types of genetic biocontrol methods proposed to reduce invasive rodents for conservation purposes might also be useful for public health.

For more information:

https://www.iaea.org/sites/default/files/20305482024.pdf
https://www.cdc.gov/rodents/index.html

Gene drive is a process that promotes or favors the inheritance of certain genes from generation to generation. It is important to understand that there are many forms of gene drive – this is an umbrella term, not a single technology. 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. Scientists first expressed the possibility of using drive systems to control pest insects in the 1950s.

Many plants and animals have two different 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 gene drive, each of those copies is equally likely to be passed to the next generation. This is often referred to as Mendelian inheritance. For a gene that displays gene drive, one of those copies would be preferentially passed to the next generation. This pattern of preferential inheritance means that in a relatively short time genes displaying drive can become highly prevalent in a population.

For more information:
https://www.geneconvenevi.org/gene-drive-timeline/
https://www.geneconvenevi.org/gene-drive-defined/
https://genedrivenetwork.org/resources/factsheets/7-factsheet-whats-a-gene-drive-july-2018-2/file
https://www.pnas.org/content/117/49/30864

https://www.isaaa.org/webinars/2021/genedrivewebinar1/default.asp

Gene drive systems are a type of genetic biocontrol in which genetic variants or genetically modified forms of a target species serve as controlling agents in a way that reduces or eliminates the threat posed by the target species. 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 eventually all or most of the individuals in a population will carry the variation. Like other forms of genetic biocontrol, uses of gene drive can be envisioned for public health, agriculture, and conservation.

For more information:

https://www.youtube.com/watch?v=rmwGqDw7AUc
https://www.geneconvenevi.org/gene-drive-defined/ ; https://www.ncbi.nlm.nih.gov/books/NBK379277/

The preferential inheritance of a gene (engineered or natural) that characterizes gene drive will cause an increase in the frequency or prevalence of the gene exhibiting gene drive 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 of the target species may eventually contain the modification. The spreading of the gene drive from its initial source individual(s) of introduction through the broader population is not unlike the ripple created when a drop of water hits a calm puddle.

Gene drives spread through mating between individuals that carry the drive system and those that don’t (wild type). All gene drive systems 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) within the interbreeding population of the target species. 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.

For more information:
https://www.who.int/publications/i/item/9789240025233

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.

For more information:

https://genedrivenetwork.org/resources/factsheets/7-factsheet-whats-a-gene-drive-july-2018-2/file
https://www.geneconvenevi.org/what-is-gene-drive/
https://www.youtube.com/watch?v=rmwGqDw7AUc

Gene drive is a genetic phenomenon and is not an “invention”. The term refers to a pattern of inheritance that is found commonly in nature. Mimicking these many examples from nature that have been known for decades, scientists are working in the laboratory to engineer gene drive systems that would introduce genetic traits into certain insects or other animals or plants such that their introduction would impact populations for the benefit of public health, conservation, or agriculture.

For more information:
https://www.geneconvenevi.org/gene-drive-timeline/

Not all gene drive-containing organisms are genetically engineered since genetic elements with drive capability occur in nature. In fact, all genomes that have been examined to date are found to contain natural gene drives. Techniques of modern molecular biology have made it possible to mimic various types of natural drives in the laboratory, and gene drive systems created using recombinant DNA technology are called engineered or synthetic gene drives.

No. Gene drive occurs frequently in nature in many organisms without any human intervention. Genomes of all organisms contain genes that display gene drive; for example, Dr Barbara McClintock was awarded the Nobel Prize in Physiology or Medicine in 1983 for her discovery of transposons or “jumping genes” which 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. We now understand that genes which can enhance their own transmission relative to other genes in the genome (natural gene drives) are not at all uncommon.

For more information:

https://www.nature.com/articles/s41467-023-37483-z#:~:text=There%20are%20some%20outside%20the,of%20risks%20that%20may%20be
https://www.geneconvenevi.org/gene-drive-timeline/

No. There are different types of gene drive, and some are built to lose their effect over a period of time (self-limiting drives). In this case, the modification is expected to disappear from the population in the absence of repeated releases of the gene drive-modified organism. Another type is described as “self-sustaining,” in which the heritable modification is intended to become stably established within interbreeding populations of the target species. This type has elicited concerns about irreversibility of population level effects. However, scientists currently are working on ways to halt or reverse the effects of such drives. While these methods have not yet been perfected, this is a recognized need and an active subject of research. (Also see “What do we know about gene drive hazards.”)

For more information:
https://www.geneconvenevi.org/articles/controlling-gene-drives/?utm_source=rss&utm_medium=rss&utm_campaign=controlling-gene-drives&utm_source=rss&utm_medium=rss&utm_campaign=controlling-gene-drives

Engineered gene drive technologies currently (2023) are in the discovery phase and are only being tested in the laboratory as part of ongoing research and development efforts. No engineered drive technologies are being used outside the laboratory. However, efforts are underway to lay the technical and regulatory groundwork to support informed decisions about the potential field testing and large-scale use of gene drive technologies.

Gene (or genome) 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 that function as molecular scissors (technically termed endonucleases – proteins that cut nucleic acids such as DNA and RNA). A popular and powerful version of molecular scissors for gene editing is the CRISPR-Cas system. Gene editing is being used for a variety of purposes, including basic scientific research and developing new treatments for diseases.

Gene editing also can be used to engineer gene drive in the laboratory. One mechanism for this 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.

For more information:

https://www.genome.gov/about-genomics/policy-issues/what-is-Genome-Editing
https://www.scientificamerican.com/video/what-is-crispr-and-why-is-it-so-important/
https://genedrivenetwork.org/videos#mxYouTubeR88da54c719d7acb5beb6a53f64c5214b-7

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 CRISPR/Cas gives researchers and engineers an unprecedented ability to control the precision and species specificity of the technology. However, other strategies also can work.

Yes. There are several ways that preferential inheritance, or drive, is achieved in nature, and some of these also can be recreated in the laboratory.

Much attention has been paid to the mechanism called “homing” for achieving gene drive. Homing endonucleases are enzymes that exist in nature that allow a gene inherited from one parent to be duplicated in the genome of its offspring so that offspring carries two copies of the gene and will pass the gene on to all of its progeny. This mechanism is a form of over-replication and can easily be mimicked using CRISPR/Cas gene editing.

For more information:

https://www.geneconvenevi.org/types-of-gene-drive/ ; https://www.youtube.com/watch?v=u5SDTnI13CM

https://www.youtube.com/playlist?list=PLbopRNGowKJ-estks1hRVkivMiP_XnAl_

Homing functions within a germline cell that will produce a sperm or an egg. It can be initiated by naturally occurring genes (homing endonuclease genes) or synthetic mimics of such genes, which code for an enzyme (endonuclease) that will recognize and cut a specific DNA sequence. In a cell that has one chromosome containing the endonuclease gene and one that doesn’t, the enzyme will create a break at the specified DNA sequence in the chromosome that doesn’t. Natural cellular repair processes result in the endonuclease gene being copied into the repaired chromosome. This very efficient creation of germline cells that have two copies of the endonuclease gene (and any associated genes, together termed the endonuclease construct) creates strong drive, because the genes now will be inherited by progeny that receive either chromosome and the copying process will continue to be repeated in those progeny. This results in preferential inheritance of the gene in subsequent generations.

The endonuclease construct can be targeted to a specific place on the opposite chromosome by adding a piece of nucleic acid that serves as a “guide.” The endonuclease construct also can be engineered to have additional functions besides producing the DNA-cutting enzyme. This might introduce an intended new characteristic (trait) into the organism. For example, a new characteristic could result from inactivation of the targeted gene into which the endonuclease construct is copied. Or alternatively, another gene coding for a new characteristic can be coupled to the endonuclease gene so that it is carried as cargo and copied into the opposite chromosome along with the endonuclease gene. This construct might also contain a genetic switch that can turn the other genes on and off at the right time in the cell cycle. With gene drive, the new characteristic can spread by mating within an interbreeding population.

For more information:

https://www.geneconvenevi.org/over-replication/

Genetic biocontrol strategies can be very species-specific. Much of this specificity rests on the species-specific mating behavior and interspecific sterility observed widely in nature. Gene drive systems depend on production of viable and fertile offspring to be passed on and thus their spreading effect requires productive mating. Genetic engineering methods can be used to enhance target species specificity at multiple levels.

However, sometimes closely related species can and do successfully interbreed. Under such circumstances, additional measures would need to be taken to enhance specificity only for the target species if that is considered necessary. These measures could include constructing the system using components that only function in the target species.

1. All engineered gene drives are assemblages of genes and associated regulatory elements needed for the gene drive system to function in the right cells, at the right time, and in the target organism. Because of the very strict temporal and spatial gene expression requirements for functional gene drives, the regulatory elements used to control gene expression are usually highly species specific.
2. Engineered gene drive constructs 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.
3. 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’.

Decreased fitness (relative competitiveness) 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 inheritance advantage gained from the gene drive is greater than any associated fitness disadvantage it might cause, the gene drive is predicted to continue to spread and increase in prevalence.

Yes. Gene drive approaches can be classified not only by the molecular mechanism used to engineer them, but also by their ability to persist and spread in the environment. The different types of gene drive technologies may have different goals. The major gene drive approaches that have been described to date (2023) are the following:

• Self-sustaining refers to a gene drive technology approach in which the heritable modification is intended to become stably established within interbreeding populations of the target species.
• Self-limiting is a gene drive technology approach 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.
• Localizing is a gene drive technology approach that would limit the spatial spread of the modification within the target population.

Different types of gene drive technologies also have different goals. Strategies that aim to reduce the population size of the target species are called population suppression (or reduction) drives. Strategies that aim to change some functional or behavioral characteristic of the target species, such as the capacity to transmit a pathogen, are called population replacement (or modification, alteration, or conversion) drives.

For more information:
https://www.who.int/publications/i/item/9789240025233
https://www.youtube.com/playlist?app=desktop&list=PLbopRNGowKJ-estks1hRVkivMiP_XnAl

This is considered highly unlikely because gene drive technology would be extremely ineffective in spreading a genetic trait through human populations. While it may be technically feasible to assemble a gene drive system that would function in human cells, that system would be very inefficient in terms of spread because humans have a relatively long generation time (20 years) and few offspring (the global average fertility rate is ~2.5 children per woman).

Gene drive should not be confused with gene editing, which is being used in some human gene therapy applications. Gene therapy involves only the genetic alteration of somatic cells (cells making up parts of the body other than sperm or eggs), and those alterations will not be transmitted to the next generation.

Yes. Resistance could develop through selection of organisms bearing a genetic change that is not susceptible to the gene drive system, similarly to how resistance arises to frequently used insecticides or drugs. Resistance is potentially a concern because it could prevent the gene drive from spreading and persisting within the target species, and reduce the desired effects of the gene drive system on that target population. In the case of gene drives for public health, this would be problematic if it happened before disease transmission could be eliminated.

For insecticides and drugs, resistance is combatted by switching between different types of products or using combinations of products. However, genetic engineering offers new ways of reducing the possibility of resistance developing in gene drive-modified organisms. Researchers are actively working to find mechanisms that will avoid or delay the development of resistance to gene drive. For example, they are targeting the gene drive system to crucial genes where a genetic change would be detrimental to the organism, and to regions of the target gene that are least likely to change.

Mosquitoes transmit many deadly and debilitating human and animal diseases. Those performing the research on gene drive technologies in mosquitoes envision several possible uses, such as: 1) to prevent transmission of malaria parasites in high incidence areas; 2) to prevent transmission of disease-causing arboviruses such as dengue or Zika in regions where they are prominent; or 3) to control transmission of avian malaria that is threatening fragile native bird populations in island habitats.

Gene drive technologies if successfully deployed in mosquitoes might be used to reduce the risk of these diseases by depleting populations of disease-carrying mosquitoes (population suppression) or reducing the ability of the mosquitoes to harbor the pathogen (population replacement or modification).

For more information:

https://www.who.int/news-room/fact-sheets/detail/vector-borne-diseases
https://www.who.int/publications/i/item/9789240025233
https://genedrivenetwork.org/videos#mxYouTubeR88da54c719d7acb5beb6a53f64c5214b-6

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, subject to development of resistance in the mosquito, and apt to miss important populations of disease-transmitting mosquitoes. Progress against malaria has plateaued in recent years, and the problem remains especially severe in Africa. Theoretical advantages of genetically modified mosquitoes are that they could do the following:

• Provide protection that benefits all people in the treated area regardless of socioeconomic status or access to healthcare facilities and without imposing additional burdens or requiring people to modify their behaviors.
• Affect only the target species directly, unlike the case with some insecticide-based methods, and thus have fewer effects on biodiversity.
• Reach mosquito populations and breeding sites that traditionally have been the hardest and most expensive to target using conventional vector control strategies, by exploiting the natural seeking behavior of the mosquitoes to find each other and oviposition sites.
• Be useful in both urban and rural environments and whether the vector is present at high or low density.
• 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.

For more information:
https://www.who.int/publications/i/item/9789240025233

https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021

Gene drive technologies could potentially enhance and enable reduced incidence of mosquito-borne diseases such as malaria in Africa and dengue fever in many parts of the world, resulting in healthier human populations. Gene drive technologies are being developed to complement other disease control tools, and may actually help the other tools to be more effective. 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 would contribute to sustainability of their protective effects.

Gene drive-modified mosquito technologies are intended to be used in integrated vector management programs, in conjunction with other control methods. Many of these activities may be incorporated into ongoing disease control plans, in which case national vector and disease control programs could play a central role in operationalizing these plans. Implementation of genetically modified mosquito technologies will involve preparatory analysis, site-specific product development, application/delivery, and post-implementation monitoring and evaluation work. Many of these functions are part of, or can build upon, current national vector control activities.

Many different 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 impactful to control than others. For example, one of the reasons why Anopheles gambiae s.s. 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 non-human animals in order to obtain the blood needed for their reproduction. Other members of the Anopheles gambiae family (sibling species) also transmit malaria, and it should be relatively straightforward to adapt the same gene drive approaches to them as well. Control of this powerful family of vectors in Africa is expected to have a large impact on malaria transmission. Similar technology could be applied to other malaria vectors.

Dengue and several other important arboviral diseases are primarily transmitted by Aedes aegypti mosquitoes, so targeting just these mosquitoes could dramatically reduce disease transmission.

There at least three reasons why gene drive systems might be considered in lieu of other genetic biocontrol techniques:

• Those that have the potential to persist and spread within and between interbreeding populations of the target organism will be better suited for control needs that extend over large areas (country or regional level).
• Genetic biocontrol methods such as the Sterile Insect Technique and related techniques require continuous rearing, transport, 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 ability of gene drive technologies to persist and spread could make them easier to deliver and maintain, contributing to their sustained impact.
• 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 flexibility is an important feature of gene drive technologies.

Mosquitoes and certain other organisms are potentially good targets for gene drive technologies because they have a short generation time and many offspring, which will allow the gene drive-associated traits to spread quickly enough to yield the desired public health effect within an observable time-frame. The generation time of mosquitoes is only a few weeks.

Molecular biology techniques are used to make the genetic construct which is to be introduced into the mosquito. The construct is then micro-injected into a mosquito egg to become incorporated into the mosquito’s DNA.

For more information:
https://www.geneconvenevi.org/how-do-you-make-a-gene-drive-mosquito/

Malaria in Africa is found from northern South Africa to the southern edge of the Sahara Desert, an enormous area. 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 complementary tools that can contribute to malaria elimination.

The Sterile Insect Technique and related genetic biocontrol programs require continuously rearing and release large numbers of insects to sustain control of the pest. While it is quite possible that these programs could contribute to malaria elimination in urban areas, they are much less suited to deal with malaria control across the abundant, remote, and highly dispersed towns and rural villages across the continent. The potential for the effects of gene drive technologies to persist for longer periods, and, in some cases to spread within and through specific malaria-transmitting mosquito species, make them attractive tools for eliminating malaria transmission over the broad region affected.

Oxitec pioneered a variation on Sterile Insect Technique using genetically engineered Aedes aegypti mosquitoes that contained genes lethal to the next generation. When the male mosquitoes were released in large numbers, local female mosquitoes which mated with them were unable to produce viable progeny and the overall numbers of Aedes aegypti mosquitoes were reduced. With this first generation product, there was no intention that the modification remain in the environment beyond the initial release. Oxitec has now moved to a second generation technology in which the introduced gene acts only against female progeny. When these modified mosquitoes are released, only male offspring survive to reproduce and these males can pass the modification to half of their offspring.

There is sometimes confusion about whether this genetic biocontrol method uses gene drive, but the answer is that it does not. This second generation technology depends on Mendelian inheritance, in which the genes from either parent usually are passed to about half of offspring in each subsequent generation. In this way, the modification will persist in the local mosquito population for some time but the numbers of modified mosquitoes will continue to decline. In contrast, the intention of gene drive is to increase the numbers of modified mosquitoes within the targeted population over time for greater sustainability and cost-effectiveness.

For more information:
https://www.oxitec.com/en/our-technology

The World Mosquito Program developed a unique strain of Aedes aegypti mosquito that is infected with the intracellular bacterium Wolbachia and this infection is transmitted from parent to progeny. Wolbachia-containing mosquitoes are much less capable of transmitting dengue and other mosquito-borne viruses. The World Mosquito Program product demonstrated significant reduction of dengue transmission in an extensive clinical trial conducted in Indonesia.

Research is underway to understand whether naturally-occurring microbes, including Wolbachia, in Anopheles mosquitoes could cause refractoriness to malaria parasites that would prevent disease transmission. Importantly, however, Wolbachia-based technologies would require larger numbers and more releases of Wolbachia-infected mosquitoes than self-sustaining and some self-limiting gene drive technologies. This might present operational and logistic limitations for the use of technologies based on Wolbachia or other symbionts against malaria across the range of conditions found in Africa.

For more information:

https://www.who.int/publications/i/item/9789240025233
https://www.worldmosquitoprogram.org/

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.

For more information:

https://bch.cbd.int/protocol/risk_assessment/cp-ra-ahteg-2020-01-04-en-2.pdf
https://www.who.int/publications/i/item/9789240025233

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.

For more information:
https://www.geneconvenevi.org/gene-drive-timeline/

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.

For more information:

https://www.twn.my/title2/books/Gene-drives.htm
https://genedrives.ch/wp-content/uploads/2019/10/Gene-Drives-Book-WEB.pdf
https://www.etcgroup.org/sites/www.etcgroup.org/files/files/etc_hbf_forcing_the_farm_web.pdf
https://www.youtube.com/watch?v=BUi6yEQhKLA.

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.

For more information:
https://www.ippc.int/en/publications/guidelines-export-shipment-import-and-release-biological-control-agents-and-other/

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):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361523/
https://malariajournal.biomedcentral.com/articles/10.1186/s12936-019-2978-5
https://genedrives.ch/wp-content/uploads/2019/10/Gene-Drives-Book-WEB.pdf
https://www.who.int/publications/i/item/9789240025233

https://malariajournal.biomedcentral.com/articles/10.1186/s12936-021-03674-6

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.
For more information:

https://www.who.int/publications/i/item/9789240025233
https://www.youtube.com/watch?v=s-dgdJQ_lO8&list=PLbopRNGowKJ8b1EJMAU53ZC46vgY4p2cz
https://www.annualreviews.org/doi/abs/10.1146/annurev-ento-020117-043154

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.

For more information:

https://www.youtube.com/playlist?list=PLbopRNGowKJ_z1k9Sqxt26ONibFCjlgKe https://www.britannica.com/animal/mosquito-insect
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378608/

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.

For more information:

https://www.geneconvenevi.org/pollination-of-plants-by-disease-vectors-a-risk-assessment/#tab-id-1
https://www.youtube.com/playlist?list=PLbopRNGowKJ_z1k9Sqxt26ONibFCjlgKe

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.

For more information:

https://www.who.int/publications/i/item/9789240025233

https://parasitesandvectors.biomedcentral.com/articles/10.1186/s13071-021-04975-0

https://www.youtube.com/playlist?list=PLbopRNGowKJ_z1k9Sqxt26ONibFCjlgKe

https://malariajournal.biomedcentral.com/articles/10.1186/s12936-021-03674-6

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 more information:

https://www.cell.com/trends/biotechnology/fulltext/S0167-7799(22)00167-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0167779922001676%3Fshowall%3Dtrue

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.

Risk analysis is a structured process for identifying, assessing, and managing potential problems, which helps to achieve the appropriate level of safety. Briefly, it consists of hazard identification, risk assessment, risk management, and risk communication. The process of risk analysis includes:

• Identifying harms that might result from the particular activity that is under consideration
• Considering the possible pathways by which that activity might cause harm to human or animal health, the environment, or socioeconomic welfare
• Evaluating the likelihood that the harm will occur and the likely consequences under scenarios relevant to the planned actions, which will characterize the risks associated with the activity
• Preparing plans to avoid or reduce any identified risks through risk management.
• Communicating with involved decision-makers and stakeholders throughout the process to enable them to identify concerns, contribute ideas, and decide upon the acceptability of any identified risks. The process culminates in decision-making by national authorities and stakeholders about the acceptability of any remaining risks in the context of potential benefits.

For more information:

https://www.who.int/publications/i/item/9789240025233
https://www.oie.int/fileadmin/Home/eng/Health_standards/aahc/2010/chapitre_import_risk_analysis.pdf
https://www.fao.org/3/ba0092e/ba0092e00.pdf

Risk assessment is a critical 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 could have a negative impact, or harm). Risk assessment is a structured and objective process to identify what hazards are relevant (hazard identification and characterization), how likely they are to happen (exposure assessment), and how significant their consequences could be (consequence assessment). Altogether, this will facilitate an understanding of the level of concern that is appropriate for each hazard.

For more information:

https://bch.cbd.int/protocol/text/ (see Annex III)
https://www.oie.int/fileadmin/Home/eng/Health_standards/aahc/2010/chapitre_import_risk_analysis.pdf
https://www.fao.org/3/ba0092e/ba0092e00.pdf

Risk assessment will take place at many different points in the development pathway, and will be conducted by:

• Product developers: The World Health Organization has recommended that developers of a gene drive technologies should conduct a risk assessment before each new testing phase or expansion of test releases, with the aim of gathering the most informative data in support of creating a safe and effective product. Developers might conduct risk assessment themselves, or may commission an external risk assessment to be conducted by experts with no vested interest in the success of the product. The results of these risk assessments will help developers understand what data they need to collect, and what 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.
• Regulators: National regulatory authorities will conduct a risk assessment as part of their review of applications submitted by developers. 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. The scope of jurisdiction for these agencies is defined by national laws, and their enabling regulations and policies. Therefore, the scope of the risk analysis for regulators is not open-ended, and is also under legally prescribed timeframes for completion.

For more information:

https://www.who.int/publications/i/item/9789240025233
https://www.ajtmh.org/view/journals/tpmd/98/6_Suppl/article-p1.xml

Risk assessments will be conducted separately for each gene drive-modified product, taking into consideration the particular conditions under which it will be tested or used. Each individual product will reflect a unique combination of characteristics – including the target species, the method of engineering, the engineered features, and the planned purpose or use – and may have a unique set of relevant hazards and risks. Because of the diversity of potential applications of gene drive technology, both the Convention on Biological Diversity and the World Health Organization have recommended that risk assessments be conducted on a case-by-case basis.

For more information:

https://genedrivenetwork.org/videos#mxYouTubeR88da54c719d7acb5beb6a53f64c5214b-1
https://www.who.int/publications/i/item/9789240025233
https://bch.cbd.int/protocol/risk_assessment/cp-ra-ahteg-2020-01-04-en-2.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531641/

Risk communication involves an interactive exchange of information and opinions throughout the risk analysis process. One component of a robust risk analysis is providing opportunities for dialogue with stakeholders in an ongoing way, with information communicated clearly and comprehensibly to facilitate active input into risk assessment and risk management planning, and inform decision-making.

Communication with potentially affected communities prior to and during the risk assessment process will help developers with framing the scope of the risk assessment, identifying concerns that should be taken into account, and determining whether to move forward. Developers will need to provide answers to community questions, adjust their plans as necessary to respond to concerns, and seek community authorization for the study to be undertaken. The mechanism for community deliberation and agreement is best determined by the community itself according to its norms.

In most national regulatory processes, the input of citizens/communities is taken into consideration during the specific public consultation phases of the decision-making process. If their input identifies scientific issues that were not adequately addressed in the environmental risk assessment, that input might trigger a reconsideration of the risk assessment. In some countries, the use of genetically modified organisms is also subject to conduct of Strategic Environmental Assessment (SEA) and Environmental and Social Impact Assessment (ESIA). SEA facilitates consideration of impacts from a general class of intervention and is designed to support policy and political decision-making. ESIA is suited to the implementation of specific projects and examines their potential positive and negative impacts in the areas of environment, socioeconomics, and health. Both SEA and ESIA require substantial stakeholder input.

For more information:

https://www.who.int/publications/i/item/978924002523

https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04183-w https://library.oapen.org/bitstream/handle/20.500.12657/30733/1/Science%20and%20the%20politics%20%20of%20openness.pdf#page=191

https://genedrivenetwork.org/videos#mxYouTubeR88da54c719d7acb5beb6a53f64c5214b-4

https://www.youtube.com/watch?v=71VYXRoz_4k
https://www.youtube.com/playlist?list=PLbopRNGowKJ9BGgg2BHu-VWYZgXpe0iLS

No. Gene drive-modified organisms possess characteristics that must be taken into account in risk assessment, such as the ability of the modification to spread into wild populations of the targeted species and the possible irreversibility of self-sustaining drives. However, several experts have expressed the opinion that these are not entirely novel and can be approached within existing risk assessment and regulatory frameworks, such as those used for other biocontrol agents and genetically modified organisms.

For more information:
https://www.isaaa.org/webinars/2022/genedrivewebinar2/default.asp
https://www.sciencedirect.com/science/article/pii/S1462901119311098?via%3Dihub
https://www.efsa.europa.eu/en/efsajournal/pub/6297

A. Mathematical and computer simulation modelling can aid in planning for data collection to inform risk assessment, and can support risk assessment and risk management by predicting the spread and efficacy of gene drive-modified organisms at large spatial scale under a range of assumptions. Modelling also can play a role in assessing some of the biosafety and cost considerations for gene drive-modified organisms.

For more information:

https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-020-00834-z

https://www.frontiersin.org/articles/10.3389/fitd.2022.828876/full

https://www.youtube.com/playlist?list=PLbopRNGowKJ9WKPho-gyrCngfAJq5EmF4

https://www.youtube.com/playlist?list=PLbopRNGowKJ9t6tPlg5dme3ljau1WgJh7

All risk assessment paradigms follow the standard accepted principles of problem formulation, hazard identification, hazard characterization, exposure and consequence assessment, and risk characterization. There are different risk assessment methodologies, however. Qualitative risk assessment uses descriptive terms to categorize assessment outputs, such as “high”, “medium”, or “low”. Semi-quantitative risk assessment evaluates risks with a score that is more reflective of probability. Quantitative risk assessment uses numbers and graphs to convey a more specific numerical estimate of risk. All methods are useful to arrive at accurate risk assessments and have both strengths and weaknesses. The critical issue is understanding the circumstances under which a particular methodology is most suitable.

For more information:

https://www.fao.org/3/i1134e/i1134e00.htm
https://www.youtube.com/playlist?list=PLbopRNGowKJ9t6tPlg5dme3ljau1WgJh7
https://www.youtube.com/playlist?list=PLbopRNGowKJ9WKPho-gyrCngfAJq5EmF4

In addition to a project-specific technical risk assessment, the regulatory authority may also require an impact assessment. The need for and extent of this requirement may be legally defined and influenced by the perceived potential for adverse effects. Some jurisdictions limit impact assessment to the analysis of effects on the biophysical environment, while others include the social, economic and cultural impacts of the project. This impact-based assessment will focus on potential adverse, neutral or beneficial changes that could result from the project, and may consider other alternatives to meet the stated need. Impact assessment can be broad in scope, covering areas of environment, socioeconomics and health.

For more information:

https://www.cbd.int/impact/

https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04183-w

https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04183-w

https://genedrivenetwork.org/videos#mxYouTubeR88da54c719d7acb5beb6a53f64c5214b-3

Before a new vector control product is brought to market, it is standardly tested in a series of expanding clinical or field trials. This phased testing pathway allows developers and regulators to learn whether the new product works and is safe to use. Research on new products begins with extensive testing in the laboratory. Developers will submit laboratory results to regulatory authorities, who will determine whether and how the product can move to clinical or field testing. Upon regulatory approval, testing will begin at a very small scale under conditions that minimize risk to people or the environment. If results from such small-scale testing look promising, regulators may approve moving to larger scale trials of safety and efficacy. Based on those results, regulators will decide whether and under what conditions the product can be made publicly available. If at any phase of the pathway the product fails to demonstrate agreed upon safety and efficacy characteristics it should not move forward, and developers will need to decide whether and how it might be improved to restart the testing process.

For more information:

https://www.fda.gov/patients/drug-development-process/step-3-clinical-research

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/what-clinical-trials-are/phases-of-clinical-trials

https://apps.who.int/iris/bitstream/handle/10665/259688/WHO-HTM-NTD-VEM-2017.03-eng.pdf

https://nap.nationalacademies.org/catalog/23405/gene-drives-on-the-horizon-advancing-science-navigating-uncertainty-and

The recommended pathway involves four phases.

• Phase 1 involves initial studies on safety and efficacy, conducted in the laboratory and in cages that contain a small number of mosquitoes. All of these studies are conducted indoors under appropriate containment to prevent escape of the modified mosquitoes into the environment. If the modified mosquitoes demonstrate the desired biological and functional characteristics, testing may move forward.
• Phase 2 expands contained testing under conditions of physical or ecological confinement, intended to limit outward migration of the modified mosquitoes by studying them in large outdoor cages or under geographic/spatial/climatic isolation. This will examine whether the modified mosquitoes continue to show expected characteristics that predict an ability to reduce disease transmission. Depending on Phase 2 results, testing may proceed to Phase 3 of revert to conduct additional studies.
• Phase 3 includes open release trials to assess performance under various disease transmission conditions. In this phase, the ability of the modified mosquitoes to reduce the incidence or prevalence of infection or disease can be directly measured. If Phase 3 testing demonstrates sufficient efficacy and safety, regulators and policy makers may consider wider implementation of the product as a public health tool.
• Phase 4 entails ongoing monitoring of the product’s effectiveness and safety under operational conditions.

Phases 1 through 3 may need to be repeated to improve the technology and refine the procedures until the requirements for moving to the next phase are met. If the genetic modification is a self-sustaining gene drive that is expected to persist in the environment, the phased testing pathway may be more realistically conceived as a continuum of expanding releases.

Decisions to move forward from one testing phase to the next will require appropriate regulatory authorization and the agreement of the communities hosting the trials.

For more information:

https://www.who.int/publications/i/item/9789240025233
http://www.ajtmh.org/content/journals/10.4269/ajtmh.18-0083

The American Committee of Medical Entomology has issued guidance for the safe handling of arthropod vectors of human and animal disease agents, including mosquitoes. These describe the facilities and training required to guard against unauthorized release from containment. They include considerations for vectors that contain recombinant DNA molecules, and those that have been modified with transgenes capable of gene drive. These recommendations take a risk-based approach, with containment requirements varying according to the potential consequences of premature releases.

For more information:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396570/
https://www.liebertpub.com/doi/10.1089/vbz.2021.0035

An important aspect of the phased testing pathway is assessing efficacy (the ability to produce the desired effect). Efficacy testing begins with measurement of entomological characteristics, such as whether the modification is stable, adversely affects the survival or mating competitiveness of the mosquitoes, and reduces either the mosquitoes’ ability to reproduce or carry the pathogen of interest. These characteristics can help predict the product’s future efficacy for preventing disease. However, the ability of the product to reduce the incidence or prevalence of infection or disease can only be assessed in subsequent large-scale field trials. These will be conducted similarly to other types of clinical trials, according to internationally agreed upon ethical standards as well as applicable national and local regulatory requirements. Pre-determined performance milestones will determine whether efficacy results justify continued testing at each phase.

For more information:

https://www.who.int/publications/i/item/9789240025233
http://www.ajtmh.org/content/journals/10.4269/ajtmh.18-0083
https://apps.who.int/iris/bitstream/handle/10665/259688/WHO-HTM-NTD-VEM-2017.03-eng.pdf

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.

For more information:

https://www.who.int/publications/i/item/9789240025233
http://www.ajtmh.org/content/journals/10.4269/ajtmh.18-0083
https://www.youtube.com/playlist?list=PLbopRNGowKJ_z1k9Sqxt26ONibFCjlgKe
https://www.youtube.com/playlist?list=PLbopRNGowKJ-UO7zxtZ3YoCKfuLKKExLv

Many existing oversight mechanisms established for other technologies will be relevant for genetically modified mosquitoes. These include mechanisms for other genetically modified organisms, for other vector control tools, and for other public health interventions. The World Health Organization (WHO) has issued guidance for testing genetically modified mosquitoes, describing considerations for safety and efficacy testing at every stage of development and implementation as well as relevant institutional and regulatory oversight bodies and policies.

For more information:
https://www.who.int/publications/i/item/9789240025233

The first level of review of plans and protocols for research and testing is likely to be performed by oversight bodies housed at the involved research institutions, although in some countries such committees may be function at the national level. 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, also known as institutional review boards or ethical review boards, provide oversight for biomedical and behavioral research involving humans with the aim of protecting the rights and welfare of research participants. Communities where testing is proposed must be consulted on and agree to the research plans.

For more information:

https://www.who.int/publications/i/item/9789240025233

https://extranet.who.int/pqweb/vector-control-products
https://apps.who.int/iris/bitstream/handle/10665/255644/WHO-HTM-GMP-2017.13-eng.pdf
https://osp.od.nih.gov/wp-content/uploads/NExTRAC-Gene-Drives-Final-Report.pdf

Government regulation of gene drive-modified mosquitoes likely will involve more than one regulatory authority, and more than one type of permit for importation and research. In countries that are Parties to the Cartagena Protocol, genetically modified organisms must be reviewed through a biosafety mechanism established under the national biosafety law. It is expected that Ministries of Health and Ministries of Environment, and possibly others, will be involved. In the US, which is not a signatory to the Cartagena Protocol, genetically modified mosquitoes aimed at reducing population size (population suppression approaches) currently are regulated by the Environmental Protection Agency, while genetically modified mosquitoes that aim to reduce vectorial capacity (population modification) are regulated by the Food and Drug Administration.

For more information:

https://www.who.int/publications/i/item/9789240025233 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10102045/
https://bch.cbd.int/protocol/background/
https://www.cbd.int/doc/legal/cartagena-protocol-en.pdf
https://www.fda.gov/media/102158/download

Because mosquitoes are mobile and gene drive is meant to spread through interbreeding populations of the targeted species, transboundary issues are relevant for gene drive-modified mosquitoes. This has raised concerns about international governance. 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.

For gene drive-modified Anopheles gambiae mosquitoes being developed to prevent malaria transmission, the target species is restricted to the African continent. Under the leadership of the African Union Development Agency (AUDA-NEPAD) mechanisms to support regional harmonization of regulatory requirements for vector control methods in Africa, including gene drive-modified mosquitoes, are under development.

For more information:

https://www.who.int/publications/i/item/9789240025233
https://onlinelibrary.wiley.com/doi/full/10.1111/reel.12289
https://www.sciencedirect.com/science/article/pii/S1877343520300890
https://www.nepad.org/microsite/integrated-vector-management-ivm

A committee of the US National Academies of Science, Engineering and Medicine, an independent non-profit organization charged with providing objective advice to inform policy making, took a close look at this question. In a 2016 report, they defined three levels of stakeholders to engage in discussion: “communities” of people who live at or near the potential testing site; “stakeholders” who live elsewhere but have direct professional or personal interests in the use of the technology; and “publics” who lack any direct connection but whose opinions may inform democratic decision making. The WHO has recently defined a strategy for ethical engagement around testing of genetically modified, including gene drive modified, mosquitoes for public health. This strategy recognizes that the ethical obligations to each of these groups differ, and thus anticipated engagement requirements also will differ. Appropriate engagement activities also will differ for different phases of testing.

For more information:

https://nap.nationalacademies.org/catalog/23405/gene-drives-on-the-horizon-advancing-science-navigating-uncertainty-and
https://www.who.int/publications/i/item/9789240025233
https://www.youtube.com/watch?v=71VYXRoz_4k
https://genedrivenetwork.org/videos#mxYouTubeRca593b85386c88963051a7d9307938e5-4

The World Health Organization has recommended that the mechanism for community deliberation and authorization should be determined by the community itself according to its norms.

• Consent: Field testing of genetic biocontrol technologies are guided by the widely recognized informed consent goal of protecting the interests of those who will be affected by the research. According to international ethics standards, individual informed consent will be a pre-requisite when personally identifiable information or biological specimens will be collected in the course of trials. For other activities, some form of community-level permission should be obtained to proceed according to conditions negotiated during the engagement process. Testing plans will be overseen by an institutional or national ethics committee (or review board), whose role is to protect the rights and welfare of research participants.
• Co-development: Co-development and knowledge integration are increasingly recognized as critical to advancement of new products. Co-development is envisioned as a process including input from the community at the proposed field site, allowing opportunity for community members to ask questions and engage in dialog with researchers, and to make suggestions or express concerns.
• Risk assessment: Risk and/or impact assessments also are expected to include community concerns and socioeconomic risks, such as any potential negative impact on basic living conditions, social structure, public health, or livelihood. Regulatory: Public consultation is a requirement for approval of activities involving GMOs in most country legislation.

For more information:

https://www.who.int/news/item/08-10-2020-launch-of-ethics-vector-borne-diseases-who-guidance
https://www.who.int/publications/i/item/9789240025233

https://www.youtube.com/playlist?list=PLbopRNGowKJ9BGgg2BHu-VWYZgXpe0iLS
https://genedrivenetwork.org/videos#mxYouTubeRca593b85386c88963051a7d9307938e5-4

https://gatesopenresearch.org/articles/5-19/v2 

https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04183-w

Surveys of attitudes in disease-endemic countries are underway. Early results suggest that people in disease endemic countries are open to the concept of genetically modified mosquitoes for public health but have concerns that will need to be addressed.

For more information:

https://allianceforscience.cornell.edu/10-things-everyone-should-know-about-gmos-in-africa/
https://www.acbio.org.za/what-does-synthetic-biology-mean-africa-africa-regional-briefing-publication-produced-etc-third
https://malariajournal.biomedcentral.com/articles/10.1186/1475-2875-9-128
https://malariajournal.biomedcentral.com/articles/10.1186/1475-2875-13-154
https://malariajournal.biomedcentral.com/articles/10.1186/s12936-019-2978-5
https://malariajournal.biomedcentral.com/articles/10.1186/s12936-020-03239-z

https://malariajournal.biomedcentral.com/articles/10.1186/s12936-021-03682-6

Many technical, safety, and policy questions remain to be addressed to ensure that gene drive technologies continue to be explored effectively, responsibly, and ethically including

• The potential for gene drive-engineered organisms to cross national borders.
• Expectations for safety and efficacy that would justify moving to field testing.
• The appropriate mechanisms for authorization of releases.

For more information:

https://www.youtube.com/watch?v=hCLYQnlH9jo
https://www.youtube.com/watch?v=CvfOxIulHRI

Gene drive technologies are being researched and developed mainly in academic institutions as evidenced from published scientific research. Some of these academic groups have spun off small biotechnology companies to pursue product development. Currently there is no evidence that major multinational companies are involved in or have an interest in gene drive technologies, especially those that are self-sustaining.

Perhaps, depending on the type of gene drive strategy and the proposed target organism.

• 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 would most likely be marketed as a public good.
• Self-limiting gene drive products and non-replicating genetic biocontrol technologies, such as SIT, 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.
• Public health products for use in developing countries are usually publicly funded and have very slim profit margins. Products for conservation purposes probably likewise will be publicly funded. Products for agricultural use might find a broader market, although this is not a given.
• Potential exists for local small business opportunities, for example providing services associated with product delivery and monitoring.

For more information:
https://ourworldindata.org/financing-healthcare

National and local government agencies and not-for-profit foundations are currently the main funders of gene drive research.

Several national agencies and international organizations have issued statements about biosafety and regulatory considerations for gene drive technologies. These include:

• The African Union High Level Panel on Emerging Technologies has formally supported research that would explore the use of this technology to control malaria.
• A number of national academic societies and government agencies have published recommendations for risk assessment of gene drive-modified organisms.
• Both the Convention on Biological Diversity and the International Union for the Conservation of Nature, in which many countries are members, are discussing gene drive technologies and new applications of synthetic biology.

For more information:

https://www.nepad.org/publication/gene-drives-malaria-control-and-elimination-africa
https://www.nepad.org/publication/position-paper-strengthening-au-member-states-regulatory-capacities-responsible
https://portals.iucn.org/library/node/48408
https://www.who.int/publications/i/item/9789240025233

The Convention on Biological Diversity (CBD) is an international agreement under the United Nations Environment Programme (UNEP) that aims to conserve biodiversity, enable the sustainable use of the components of biodiversity, and enable fair and equitable sharing of benefits arising out of the utilization of genetic resources. 196 countries currently (2022) are Parties to this agreement. The CBD considers organisms containing engineered gene drives as Living Modified Organisms (LMOs; also 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. The CBD has thus far recommended that a precautionary approach should be taken with regard to decisions on activities in the field and recommended further consideration of risk assessment methods. Work is underway under the CPB to develop additional voluntary guidance materials to support case-by-case risk assessment of living modified organisms
containing engineered gene drives.

For more information:

https://www.cbd.int/

https://www.cbd.int/doc/c/a763/e248/4fa326e03e3c126b9615e95d/cp-ra-ahteg-2020-01-05-en.pdf

https://www.cbd.int/doc/c/2c62/5569/004e9c7a6b2a00641c3af0eb/cop-14-l-31-en.pdf

https://www.youtube.com/playlist?list=PLbopRNGowKJ-LM6kEKvmwe5WZA30fR6G6 

https://www.cbd.int/doc/c/c750/0f0a/6cd323ebe26a29d55f4e294b/cp-mop-10-l-08-en.pdf

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 often interpreted to mean that if there is uncertainty regarding 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 when uncertainty about safety remains.

This perspective assumes that the status quo always is preferable to a new activity that may carry risks.

For more information:

https://www.un.org/en/development/desa/population/migration/generalassembly/docs/globalcompact/A_CONF.151_26_Vol.I_Declaration.pdf
https://iepi.mcmaster.ca/research/pillars-of-research/infectious-disease-management/research-syntheses/precautionary-principle/

Membership of the International Union for the Conservation of Nature (IUCN) consists of States and government agencies as well as other organizations and institutions with interest in nature conservation. IUCN recently issued a report on the potential use of synthetic biology, including gene drives, for conservation recognizing the need for case-by-case assessments and decision-making for each different application of synthetic biology. Discussions are ongoing regarding the development of an IUCN policy on the implications of synthetic biology in nature conservation.

For more information:

https://www.iucn.org/theme/science-and-economics
https://portals.iucn.org/library/node/48408
https://www.iucncongress2020.org/motion/075

Conventional control methods include drugs to prevent or treat human infection and disease, vector control tools based on chemical pesticides such as spatial application of insecticides and use of insecticide-impregnated nets, as well as environmental management efforts to decrease the habitat where vectors breed and housing improvement to reduce human exposure.

These methods are all important, but they have not been able to fully solve the public health problem posed by vector borne diseases. Conventional vector control methods can be extremely costly to maintain and insecticide resistance is a problem in the mosquitoes that transmit either malaria or common arboviral diseases. It is widely recognized that current tools likely will be insufficient to eradicate malaria. For example, the World Health Organization reports that progress against malaria has plateaued in recent years and the situation remains precarious, especially in sub-Saharan Africa. They also report that global incidence of dengue has grown dramatically, with about half the world’s population at risk from dengue and other viral diseases carried by the same mosquito species.

For more information:

https://www.who.int/news-room/fact-sheets/detail/malaria

https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2021

https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue   

Genetic biocontrol approaches are being considered to address several global problems that, despite our best efforts, have proven difficult to solve by other available means. By modifying or reducing the numbers of arthropod vectors, they could contribute to preventing transmission of infectious diseases causing illness and death to millions of people worldwide. For agriculture, similar technologies could help to reduce crop loss caused by insect pests, recently estimated to cost the world over $70 billion per year annually. For conservation, they have been proposed as a method for controlling invasive species that likewise cause enormous economic losses and threaten biodiversity.

Genetic biocontrol can be used in combination with other methods, offering a new chance to bring these global challenges under control.

For more information:

https://www.who.int/news-room/fact-sheets/detail/vector-borne-diseases

https://www.mdpi.com/2414-6366/8/4/201

https://www.fao.org/news/story/en/item/1187738/icode/

https://www.geneticbiocontrol.org/

https://www.iucn.org/resources/issues-briefs/invasive-alien-species-and-sustainable-development

https://www.mdpi.com/2414-6366/8/4/201

Chemical pesticides are very commonly used for pest control in agriculture, although the degree of dependence varies by country. This includes insecticides for insect pests, herbicides for weeds, and fungicides for plant pathogens. Various types of good farming practices, such as crop rotation and integrated pest management programs, offer approaches intended to reduce pesticide dependence. Organic production employs many of the same concepts but avoids use of synthetic pesticides entirely. Classical biocontrol methods involving dissemination of natural enemies have demonstrated promise for reducing damage by invasive insect pests. Sterile Insect Technique, which employs dissemination of radiation-sterilized pest insects to reduce productive mating and thereby diminish pest population size, has been deployed against several agricultural pests, perhaps most widely for screw worm and Mediterranean fruit fly. Additionally, there has been increasing interest in bioengineered crops, such as those containing a gene from the soil bacterium Bacillus thuringiensis that makes them insect resistant.

Nonetheless, the Food and Agriculture Organization estimates that between 20 to 40 percent of global crop production is lost to pests annually. Extensive exposure to synthetic and organic pesticides has raised concerns about their adverse effects upon the environment and human health, and fosters the emergence of resistance that necessitates increased usage and ongoing development of new alternatives. Global food insecurity is an ongoing challenge, which climate change may only exacerbate.

For more information:

https://link.springer.com/article/10.1007/s42452-019-1485-1;

https://www.epa.gov/safepestcontrol/integrated-pest-management-ipm-principles; https://www.fao.org/news/story/en/item/1187738/icode/; https://www.ers.usda.gov/topics/farm-practices-management/crop-livestock-practices/pest-management.aspx#:~:text=U.S.%20farmers%20employ%20a%20range,apply%20organic%20and%20synthetic%20pesticides; https://www.fao.org/state-of-food-security-nutrition

Invasive alien species are non-native animals, plants or other organisms that have been accidentally or purposely introduced in areas outside their natural range, become established in these new areas, and cause damage to native biodiversity resulting in substantial socio-economic costs. The direct impact of alien invasive species is estimated to cost the global economy billions of dollars annually.

Accidental introductions can result from international trade and transportation. The best method to control the damage done by invasive alien species is considered to be prevention through early detection and rapid response to eradicate the new species before it can become locally established. If that is not possible, control and management options include biological control using natural enemies of the invasive species, chemical control using pesticides and toxicants, and various types of mechanical or physical control to make the environment less hospitable to the new species. Educational efforts to increase awareness and use of practices aimed at preventing the spread of the invasive species also may be helpful. Nevertheless, the International Union for the Conservation of Nature warns that the rate of new introductions is increasing and their impacts on food security, health and biodiversity may be compounded by climate change.

For more information:

https://www.invasivespeciesinfo.gov/subject/control-mechanisms#:~:text=Chemical%20control%20includes%20the%20use,crops%2C%20changing%20planting%20dates); https://www.iucn.org/resources/issues-briefs/invasive-alien-species-and-sustainable-development; https://www.geneticbiocontrol.org/

Due to their isolation from the mainland, islands often harbor a high proportion of specialized native plants and animals that contribute to the world’s biodiversity. Introduced invasive species, such as rats and feral cats, pose a serious threat to fragile island ecosystems and wildlife, especially birds. It has been estimated that over the past 500 years, invasive alien species have contributed to nearly half of global bird extinctions.

Genetic biocontrol methods are under consideration for certain vertebrate pests that present particularly difficult ecological and economic challenges on islands. For example, removal of invasive rodents from islands has proven to be a highly impactful conservation intervention. However, currently effective methods for doing so are limited largely to use of rodenticides, which have other ethical, ecological, social, and financial constraints. Genetic biocontrol methods that could suppress the island rodent population by reducing reproductive capacity have been proposed as a possible alternative that would be more humane and sustainable. Research on genetic biocontrol of rodents and other island pest vertebrates is underway but still at an early stage.

Introduced pathogens also present a well-recognized risk to island biodiversity. Avian malaria is an introduced disease known to threaten native birdlife in Hawaii. Since this pathogen is transmitted by mosquitoes, it may be susceptible to similar genetic biocontrol methods being developed for vector-borne human diseases.

For more information:

https://www.cbd.int/island/invasive.shtml

https://www.aphis.usda.gov/aphis/maps/sa_wildlife_services/ws-managing-invasive-species

https://www.geneticbiocontrol.org/

https://portals.iucn.org/library/efiles/documents/2019-012-En.pdf

https://royalsociety.org.nz/assets/Uploads/Gene-editing-in-pest-control-technical-paper.pdf

https://www.frontiersin.org/articles/10.3389/fagro.2021.806569/full

 Most research has been conducted in Anopheles gambiae (Anopheles gambiae s.s. and Anophleles coluzzii) mosquitoes thus far, which are important vectors of malaria in Africa. Aedes aegypti mosquitoes, which are important vectors of arboviral infections,  have not proven to be as amenable to CRISPR/Cas-mediated homing gene drive systems as Anopheles. However, CRISPR-based drive systems have recently shown success in the laboratory and antiviral effector genes for population replacement have been identified. Work to apply gene drive technology to Culex mosquitoes, which transmit a number of human and animal diseases, is at an even earlier stage but tools to support genome editing have been developed.

For more information: https://elifesciences.org/articles/51701; https://www.mdpi.com/2075-4450/11/1/52; https://www.biorxiv.org/content/10.1101/2021.12.08.471839v1; https://www.nature.com/articles/s41467-021-23239-0

Yes, depending upon the type of gene drive and extent of release. Gene drive does not cause or increase insecticide resistance. 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. Additional methods for controlling gene drive-modified mosquitoes, including genetic mechanisms and small molecule approaches, also are being explored.

For more information:

https://www.ajtmh.org/view/journals/tpmd/98/6_Suppl/article-p1.xml

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;

https://www.beiresources.org/AnophelesProgram/TrainingMethods.aspx

Phase 1 studies can be conducted in appropriately contained laboratory and cage facilities anywhere, as long as the mosquito species of interest can be maintained there. All field studies and trials will necessarily have to be conducted in environments where the target mosquito species exists naturally. Phase 3 testing, which measures safety and efficacy for reducing disease, must be conducted in areas where the disease of interest is actively transmitted.

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.

Genetically modified mosquitoes are developed using genetic engineering. Gene drive-modified mosquitoes are a type of genetically modified-mosquitoes. In both cases, mosquitoes of the targeted species are modified 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.

Several genetic modification approaches are being explored, from those that will have no lasting effect on the targeted vector population after release to those that are intended to introduce a more persistent change. 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/

Gene drive is a process that promotes or favors the inheritance of certain genes from one generation to the next. Since the early 20^th century, scientists have discovered several types of “selfish genetic elements” that are present naturally in the genomes of many species. These naturally occurring genetic elements are able to enhance their own transmission relative to the rest of the genes in the genome regardless of whether their presence is neutral or even harmful to the individual organism as a whole, and thus they exhibit drive and are called “natural gene drives.” Examples of natural gene drives include homing endonuclease genes found in all forms of microbial life, transposable elements found in many plants and animals, and meiotic drive also found in various plants and animals.

Synthetic gene drives utilize techniques of modern molecular biotechnology to achieve effects similar to those seen with natural gene drives in a wider range of organisms. Thus organisms carrying synthetic gene drive(s) are considered genetically engineered/modified, though the synthetic drive mechanism they carry may function very comparably to a natural gene drive. Synthetic gene drives can be used to introduce new traits into a population of organisms, such as mosquitoes or mice, over just a few generations.

For more information:https://www.geneconvenevi.org/types-of-gene-drive/

https://www.science.org.au/support/analysis/reports/synthetic-gene-drives-australia-implications-emerging-technologies/appendix

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

https://genedrivenetwork.org/videos#mxYouTubeR88da54c719d7acb5beb6a53f64c5214b-7

A hazard is any potential source of harm, or adverse effect, to something or someone. Risk is the probability of harm due to a particular hazard.

Hazard identification is an early step in risk assessment, which attempts to comprehensively identify all the characteristics or conditions that might possibly lead to the occurrence of a negative outcome i.e. a harm. In a subsequent step, the likelihood of that harm occurring under certain defined conditions and the magnitude (seriousness) of that harm if it did occur are considered together to determine the risk due to that hazard. Thus, during risk assessment, it may be determined that an identified hazard does not pose significant or unacceptable risk.

For more information: https://www.youtube.com/watch?v=_GwVTdsnN1E

Although there are major ethical as well as technical reasons not to consider using gene drive in humans, some scientists have speculated about ways that gene drive might be used to prevent a population of animals from becoming infected with pathogens that could sicken them and/or subsequently be transmitted to people. Animals can serve as a “reservoir” for some diseases, meaning that the disease-causing pathogen can live, grow and multiply in the animal. Depending on the type of pathogen, humans may be able to catch the disease either directly from the animal reservoir (such as through a bite, ingestion of infected meat, or interaction with pathogen-containing animal excrement in the environment) or indirectly via the intervention of a vector, such as a mosquito or a flea, that carries the pathogen between the animal and the human. Gene drive has been proposed as a possible way to spread a resistance trait through the target population of animals, analogous to immunizing or “vaccinating” the animals against the pathogen. This could both protect the animal and ultimately reduce the risk of human exposure to the pathogen. Examples of proposed uses include making bats resistant to coronaviruses or mice resistant to Lyme disease. However, this concept is still in a very preliminary stage of development.

For more information:

https://www.statnews.com/2021/07/01/could-editing-genomes-of-bats-prevent-future-coronavirus-pandemics-two-scientists-think-its-worth-a-try/

https://www.media.mit.edu/projects/preventing-tick-borne-disease-by-permanently-immunizing-mice/overview/

Typically, risk assessment utilizes a variety of data and information sources, giving them different weight. Data generated using the particular organism (species), modification (engineered trait), and receiving environment will have the highest weight. To date, no gene drive-modified organism has been released into the environment. Experimental data from contained testing in small and large cages will be most informative, along with knowledge of the biology and behavior in nature of the host insect, of related naturally occurring gene drives, and of the environment where the modified insects will be used. Various predictive tools, including mathematical modelling, can provide insights into aspects of the behavior of the gene drive-modified insects upon release, such how time, seasonality, or use of other control measures might affect their spread through the local population of the target organism. Nonetheless, in the initial absence of data on the field performance of engineered gene drives, risk assessment may have to accommodate a range of uncertainties. Some of these may be addressable through specific risk mitigation methods and monitoring. While, several risk assessment experts have published that current risk assessment frameworks are suitable for evaluating gene drive-modified organisms, they also have noted areas where additional guidance would be helpful. Work to provide such guidance is underway in several venues, including the Convention on Biological Diversity and the European Food Safety Authority. This will add to existing internationally accepted risk assessment guidelines.

For more information:

https://www.sciencedirect.com/science/article/abs/pii/S1462901119311098

https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2020.6297

https://bch.cbd.int/protocol/risk_assessment/cp-ra-ahteg-2020-01-04-en-2.pdf

https://www.nature.com/articles/s41467-023-37483-z

https://www.liebertpub.com/doi/10.1089/vbz.2019.2606?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed

https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04183-w

https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2017.4971

The WHO Guidance Framework for Testing Genetically Modified Mosquitoes calls for monitoring of efficacy and safety at each phase of testing as well as a period of post-implementation monitoring for ongoing effectiveness and safety under operational conditions after a decision is made to deploy gene drive-modified mosquitoes as public health tools (also see How will mosquitoes with gene drive be tested?). The Guidance Framework provides specific recommendations on the types of data that can be collected at each phase.

For more information:

https://www.who.int/publications/i/item/9789240025233

National regulators will determine monitoring requirements as part of the approval process for release of gene drive-modified mosquitoes, according to relevant laws, implementing regulations, and policies. In general, potential harms associated with the proposed activities will be characterized during case-specific pre-release risk assessment. Pertinent information, such as prior experience with gene drive-modified and other related genetically modified mosquitoes as well as knowledge of the biology and behavior or the mosquito species, of the modified trait(s), and of the receiving environment (geography, weather, land use, built environment, etc.) will be considered in the risk characterization. Regulatory authorities will provide a recommendation of acceptable risks and those that need to be managed or mitigated, as well as any strategies to provide such management or mitigation. These recommendations will form the basis for the terms of reference for use of an approved gene drive-modified mosquito product. Once approved and released, it will be necessary to monitor the effectiveness and sufficiency of the risk management measures. Thus, requirements of post-approval monitoring are expected to focus largely on those issues where there is ongoing uncertainty about safety and efficacy that was not resolved during risk assessment. Monitoring endpoints, frequency, and duration can be altered based on post-approval data resolving the remaining uncertainty.

No. Unlike Sterile Insect Technique (SIT) that depends on overflooding the local target mosquito population to be effective, gene drive-modified mosquitoes are expected to be capable of establishing and achieving their stated objective when released in lower numbers. While the size and frequency of releases may be greater for self-limiting gene drive approaches than for self-sustaining approaches, in either case the numbers will not be as large as those used in SIT.

Conventional and genetically modified mosquito biocontrol measures have generally aimed for male only releases to minimize biting nuisance and potential to transmit disease. It is anticipated that gene drive-modified mosquito releases will operate under similar conditions. Any potential harms that might be associated with release of male mosquitoes should be considered in risk assessment.

This would require that the engineered gene drive construct enter and be functional within germline cells of an unrelated species. It is expected that case-specific risk assessment will find this possibility to be highly improbable because it would require a series of extremely unlikely events to occur. Nevertheless, the possibility of such “horizontal transfer” or “horizontal gene flow” should be considered in case-specific risk assessment (see examples below).

For more information:

https://malariajournal.biomedcentral.com/articles/10.1186/s12936-021-03674-6

https://publications.csiro.au/rpr/download?pid=csiro:EP151689&dsid=DS2