How do gene drives work?
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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.
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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.
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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.
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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.
- 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.
- 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.
- In addition to the Cas enzyme acting on the correct sequence, the hundreds of bases of DNA flanking the site on the chromosome cut by Cas also need to be sufficiently specific to the intended target gene in order to achieve ‘drive’.
How can a gene drive spread if it causes a decrease in the fitness of the organism that carries it?
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.
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.
How can scientists know whether a genetically modified-mosquito product successfully prevents disease?
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.
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What is the difference between genetically modified-mosquitoes and gene drive-modified mosquitoes?
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 20th 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/
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