Gene drive

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A gene drive is a genetic engineering technology that can propagate a particular suite of genes throughout a population.[1] Gene drives can arise through a variety of mechanisms.[2] They have been proposed to provide an effective means of genetically modifying specific populations and entire species.

The technique can employ adding, deleting, disrupting, or modifying genes.[3][4] Gene drives affect only sexually reproducing species, excluding viruses or bacteria.

Applications include exterminating insects that carry pathogens (notably mosquitoes that transmit malaria, dengue and zika pathogens), controlling invasive species or eliminating herbicide or pesticide resistance.[5][3][6]

As with any potentially powerful technique, gene drives can be misused in a variety of ways or induce unintended consequences. For example, a gene drive intended to affect only a local population might spread across an entire species. Many non-native species have a high likelihood of returning to their original habitats, through natural migration, environmental disruption (storms, floods, etc.), accidental human transportation, or purposeful relocation. Specimens whose reproduction/survival is compromised that somehow return to their native habitat, could unintentionally drive their species to extinction.[7]

Several molecular mechanisms can mediate a gene drive.[8] Naturally occurring mechanisms arise when alleles evolve molecular mechanisms that give them a transmission chance greater than (the normal) 50%.

Mechanism[edit]

In sexually-reproducing species, most genes are present in two copies (which can be the same or different alleles), each of which has a 50% chance of passing to a descendent. For a particular allele to spread through a large population, it must increase the fitness of those who carry it. However, some alleles have evolved molecular mechanisms that confer on them a greater chance of transmission. This allows them to spread through a population even if they reduce fitness. By biasing the inheritance of particular altered genes, synthetic gene drives could spread alterations through a population.[3][4]

Molecular mechanisms[edit]

Molecular mechanism of gene drive.
Molecular mechanism of gene drive.

At the molecular level, an endonuclease gene drive works by cutting a chromosome at a specific site that does not encode the drive, inducing the cell to repair the damage by copying the drive sequence onto the damaged chromosome. The cell then has two copies of the drive sequence. The method derives from genome editing techniques and relies on the fact that double strand breaks are most frequently repaired by homologous recombination, (in the presence of a template), rather than non-homologous end joining. To achieve this behavior, endonuclease gene drives consist of two nested elements:

  • either a homing endonuclease or a RNA-guided endonuclease (e.g., Cas9 or Cpf1[9]) and its guide RNA, that cuts the target sequence in recipient cells
  • a template sequence used by the DNA repair machinery after the target sequence is cut. To achieve the self-propagating nature of gene drives, this repair template contains at least the endonuclease sequence. Because the template must be used to repair a double-strand break at the cutting site, its sides are homologous to the sequences that are adjacent to the cutting site in the host genome. By targeting the gene drive to a gene coding sequence, this gene will be inactivated; additional sequences can be introduced in the gene drive to encode new functions.

As a result, the gene drive insertion in the genome will re-occur in each organism that inherits one copy of the modification and one copy of the wild-type gene. If the gene drive is already present in the egg cell (e.g. when received from one parent), all the gametes of the individual will carry the gene drive (instead of 50% in the case of a normal gene).[3]

Spreading in the population[edit]

Since it can never more than double in frequency with each generation, a gene drive introduced in a single individual typically requires dozens of generations to affect a substantial fraction of a population. Alternatively, releasing drive-containing organisms in sufficient numbers can affect the rest within a few generations; for instance, by introducing it in every thousandth individual, it takes only 12–15 generations to be present in all individuals.[10] Whether a gene drive will ultimately become fixed in a population and at which speed depends on its effect on individuals fitness, on the rate of allele conversion, and on the population structure. In a well mixed population and with realistic allele conversion frequencies (≈90%), population genetics predicts that gene drives get fixed for selection coefficient smaller than 0.3;[10] in other words, gene drives can be used not only to spread modifications as long as reproductive success is not reduced by more than 30%. This is in contrast with normal genes, which can only spread across large populations if they increase fitness.

Technical limitations[edit]

Because gene drives propagate by replacing other alleles that contain a cutting site and the corresponding homologies, their application is limited to sexually reproducing species (because they are diploid or polyploid and alleles are mixed at each generation). As a side effect, inbreeding could in principle be an escape mechanism, but the extent to which this can happen in practice is difficult to evaluate.[11]

Due to the number of generations required for a gene drive to affect an entire population, the time to universality varies according to the reproductive cycle of each species: it may require under a year for some invertebrates, but centuries for organisms with years-long intervals between birth and sexual maturity, such as humans.[12] Hence this technology is of most use in fast-reproducing species.

Issues[edit]

Issues highlighted by researchers include:[13]

  • Mutations: A mutation could happen mid-drive, which has the potential to allow unwanted traits to "ride along".
  • Escape: Cross-breeding or gene flow potentially allow a drive to move beyond its target population.
  • Ecological impacts: Even when new traits' direct impact on a target is understood, the drive may have side effects on the surroundings.

The Broad Institute of MIT and Harvard added gene drives to a list of uses of gene-editing technology it doesn't think companies should pursue.[14]

Bioethics concerns[edit]

Gene drives affect all future generations and represent the possibility of a larger change in a living species than has been possible before.[15]

In December 2015, scientists of major world academies called for a moratorium on inheritable human genome edits that would affect the germline, including those related to CRISPR-Cas9 technologies,[16] but supported continued basic research and gene editing that would not affect future generations.[17] In February 2016, British scientists were given permission by regulators to genetically modify human embryos by using CRISPR-Cas9 and related techniques on condition that the embryos were destroyed in seven days.[18][19] In June 2016, the US National Academies of Sciences, Engineering, and Medicine released a report on their "Recommendations for Responsible Conduct" of gene drives.[20]

Models suggest that extinction-oriented gene drives will wipe out target species and that drives could reach populations beyond the target given minimal connectivity between them.[21]

Esvelt stated that an open conversation was needed around the safety of gene drives: "In our view, it is wise to assume that invasive and self-propagating gene drive systems are likely to spread to every population of the target species throughout the world. Accordingly, they should only be built to combat true plagues such as malaria, for which we have few adequate countermeasures and that offer a realistic path towards an international agreement to deploy among all affected nations."[22]. He moved to an open model for his own research on using gene drive to eradicate Lyme disease in Nantucket and Martha's Vineyard.[23] Esvelt and colleagues suggested that CRISPR could be used to save endangered wildlife from extinction. Esvelt later retracted his support for the idea, except for extremely hazardous populations such as malaria-carrying mosquitoes and isolated islands that would prevent the drive from spreading beyond the target area.[24]

History[edit]

Austin Burt, an evolutionary geneticist at Imperial College London, introduced the possibility of conducting gene drives based on natural "selfish" homing endonuclease genes in 2003.[4]

Researchers had already shown that such “selfish” genes could spread rapidly over successive generations. Burt suggested that gene drives might be used to prevent a mosquito population from transmitting the malaria parasite or to crash a mosquito population. Gene drives based on homing endonucleases have been demonstrated in the laboratory in transgenic populations of mosquitoes[25] and fruit flies.[26][27] However, homing endonucleases are sequence-specific. Altering their specificity to target other sequences of interest remains a major challenge.[8] The possible applications of gene drive remained limited until the discovery of CRISPR and associated RNA-guided endonucleases such as Cas9 and Cpf1.

In June 2014, the World Health Organization (WHO) Special Programme for Research and Training in Tropical Diseases[28] issued guidelines[29] for evaluating genetically modified mosquitoes. In 2013 the European Food Safety Authority issued a protocol[30] for environmental assessments of all genetically modified organisms.

Cayman Islands[edit]

In the Cayman Islands Oxitec started releases in summer 2016.

As of early 2017 8 million specimens had been released in West Bay. Preliminary data showed that the drive males were successfully mating with local females. The fluorescent marker for the drive showed up in 94 percent of larvae collected in the targeted zone, demonstrating they had out-competed males in the wild for mates. Egg counts had been reduced by 88 percent.[31] The result was a 62 percent suppression rate of the virus-carrying mosquitoes, according to data provided by officials there. About 400,000 insects are released there weekly.[32]

Florida Keys[edit]

In August 2016 the U.S. Food And Drug Administration (FDA) issued a “Finding of No Significant Impact" (FONSI) to biotech company Oxitec's plan to release genetically modified male Aedes aegypti (mosquitoes) into the Florida Keys. The intent was to stop the spread of mosquito-borne diseases, including Zika. The modification adds a gene that kills offspring before they reach reproductive age. The mosquitoes need the antibiotic tetracycline to survive. Oxitec must obtain approval from the Florida Keys Mosquito Control District before conducting a drive.[33] The drive did not occur because of local opposition. The company needs approval from the US Environmental Protection Agency to proceed. Oxitec submitted a new application to the EPA in December and the EPA had seven months to decide whether to issue an experimental-use permit.[32]

Funding[edit]

The Bill and Melinda Gates Foundation invested $75 million in gene drive technology. The foundation originally estimated the technology to be ready for field use by 2029 somewhere in Africa. However, in 2016 Gates changed this estimate to some time within the following two years.[34] In December 2017, documents released under the Freedom of Information Act showed that DARPA had invested $100 million in gene drive research.[35]

Predator Free 2050[edit]

In July 2016, New Zealand's prime minister John Key announced Predator Free 2050. In January 2017 it was announced that gene drives would be used in the effort.[36] In 2017 one group in Australia and another in Texas released preliminary research into creating 'daughterless mice', using gene drives in mammals; these mice are considered particularly useful for New Zealand and other islands overrun with invasive mammals.[37]

California[edit]

In 2017 scientists at the University of California, Riverside developed a gene drive to attack the invasive spotted-wing drosophila, a type of fruit fly native to Asia that is costing California's cherry farms $700 million per year because of its tail's razor-edged “ovipositor” that destroys unblemished fruit. The primary alternative control strategy involves the use of insecticides called pyrethroids that kills almost all insects that it contacts.[14]

Control strategies[edit]

Scientists have designed multiple strategies to maintain control over gene drives.

The drosophila drive requires at least thousands of insects for the drive to begin. A few individuals escaping the target region would be unlikely to spread the drive.[37]

CRISPR[edit]

CRISPR[38] is a DNA editing method that makes genetic engineering faster, easier and more efficient.[39] The approach involves expressing an RNA-guided endonuclease such as Cas9 along with guide RNAs directing it to a particular sequence to be edited. When the endonuclease cuts the target sequence, the cell repairs the damage by replacing the original sequence with homologous DNA. By introducing an additional template with appropriate homologues, an endonuclease can be used to delete, add or modify genes in an unprecedentedly simple manner. As of 2014, it had been tested in cells of 20 species, including humans.[3] In many of these species, the edits modified the organism's germline, allowing them to be inherited.

In 2014 Esvelt and coworkers first suggested that CRISPR/Cas9 might be used to build endonuclease gene drives.[3] In 2015 researchers published successful engineering of CRISPR-based gene drives in Saccharomyces[40], Drosophila[41] and mosquitoes.[42][43] All four studies demonstrated efficient inheritance distortion over successive generations, with one study demonstrating the spread of a gene drive into laboratory populations.[43] Drive-resistant alleles were expected to arise for each of the described gene drives, however this could be delayed or prevented by targeting highly conserved sites at which resistance is expected to have a severe fitness cost.

Because of CRISPR's targeting flexibility, gene drives could theoretically be used to engineer almost any trait. Unlike previous designs, they could be tailored to block the evolution of drive resistance in the target population by targeting multiple sequences within appropriate genes. CRISPR could permit a variety of gene drive architectures intended to control rather than crash populations.[citation needed]

Applications[edit]

Gene drives have two main classes of application, which have implications of different significance:

  • introduce a genetic modification in laboratory populations; once a strain or a line carrying the gene drive has been produced, the drive can be passed to any other line by mating. Here the gene drive is used to achieve much more easily a task that could be accomplished with other techniques.
  • introduce a genetic modification in wild populations. Gene drives constitute a major development that makes possible previously unattainable changes.

Because of their unprecedented potential, safeguard mechanisms were proposed and tested.[40] [44]

Disease vector species[edit]

One possible application is to genetically modify mosquitoes and other disease vectors so that they cannot transmit diseases such as malaria and dengue fever. Researchers claimed that by applying the technique to 1% of the wild population of mosquitoes, they could eradicate malaria within a year.[45]

Invasive species[edit]

A gene drive could be used to eliminate invasive species and has, for example, been proposed as a way to eliminate invasive species in New Zealand.[46] In response, many scientists objected to the technique, fearing it could spread and wipe out species in native habitats.[47] The gene could mutate, potentially causing unforeseen problems (as could any gene).[48] Many non-native species can hybridize with native species, such that a gene drive afflicting a non-native plant or animal that hybridizes with a native species could doom the native species. Many non-native species have naturalized into their new environment so well that crops and/or native species have adapted to depend on them. [49]

Predator Free 2050[edit]

The Predator Free 2050 project, is a New Zealand government program to completely eliminate eight invasive mammalian predator species (rats, short-tailed weasels, and possums) from the country by 2050.[50][36]

See also[edit]

References[edit]

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External links[edit]