Gene drive


A gene drive is a genetic engineering technology that propagates a particular suite of genes throughout a population by altering the probability that a specific allele will be transmitted to offspring from the natural 50% probability. Gene drives can arise through a variety of mechanisms. 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.
Proposed applications include exterminating insects that carry pathogens, controlling invasive species or eliminating herbicide or pesticide resistance.
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. Gene drives used to eradicate populations of invasive species in their non-native habitats may have consequences for the population of the species as a whole, even in its native habitat. Any accidental return of individuals of the species to its original habitats, through natural migration, environmental disruption, accidental human transportation, or purposeful relocation, could unintentionally drive the species to extinction if the relocated individuals carried harmful gene drives.
Gene drives can be built from many naturally occurring selfish genetic elements that use a variety of molecular mechanisms. These naturally occurring mechanisms induce similar segregation distortion in the wild, arising when alleles evolve molecular mechanisms that give them a transmission chance greater than the normal 50%.

Mechanism

In sexually-reproducing species, most genes are present in two copies, either one of which has a 50% chance of passing to a descendant. By biasing the inheritance of particular altered genes, synthetic gene drives could spread alterations through a population.

Molecular mechanisms

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,, rather than non-homologous end joining. To achieve this behavior, endonuclease gene drives consist of two nested elements:
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, all the gametes of the individual will carry the gene drive.

Spreading in the population

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. 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, population genetics predicts that gene drives get fixed for selection coefficient smaller than 0.3; in other words, gene drives can be used 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

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. 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.
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. Hence this technology is of most use in fast-reproducing species.

Issues

Issues highlighted by researchers include:
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.

Bioethics concerns

Gene drives affect all future generations and represent the possibility of a larger change in a living species than has been possible before.
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, but supported continued basic research and gene editing that would not affect future generations. 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. In June 2016, the US National Academies of Sciences, Engineering, and Medicine released a report on their "Recommendations for Responsible Conduct" of gene drives.
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.
Kevin M. 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.". He moved to an open model for his own research on using gene drive to eradicate Lyme disease in Nantucket and Martha's Vineyard. 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.

History

Austin Burt, an evolutionary geneticist at Imperial College London, introduced the possibility of conducting gene drives based on natural homing endonuclease selfish genetic elements in 2003.
Researchers had already shown that such genes could act selfishly to 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 and fruit flies. However, homing endonucleases are sequence-specific. Altering their specificity to target other sequences of interest remains a major challenge. 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 Special Programme for Research and Training in Tropical Diseases issued guidelines for evaluating genetically modified mosquitoes. In 2013 the European Food Safety Authority issued a protocol for environmental assessments of all genetically modified organisms.

Funding

, a project funded by 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. In December 2017, documents released under the Freedom of Information Act showed that DARPA had invested $100 million in gene drive research.

Control strategies

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.

CRISPR

is a DNA editing method that makes genetic engineering faster, easier, and more efficient. 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., it had been tested in cells of 20 species, including humans. 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. In 2015 researchers published successful engineering of CRISPR-based gene drives in Saccharomyces, Drosophila, and mosquitoes. All four studies demonstrated efficient inheritance distortion over successive generations, with one study demonstrating the spread of a gene drive into laboratory populations. 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.

Applications

Gene drives have two main classes of application, which have implications of different significance:
Because of their unprecedented potential risk, safeguard mechanisms have been proposed and tested.

Disease vector species

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 have claimed that by applying the technique to 1% of the wild population of mosquitoes, that they could eradicate malaria within a year.

Invasive species control

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. Gene drives for biodiversity conservation purposes are being explored as part of The Genetic Biocontrol of Invasive Rodents program because they offer the potential for reduced risk to non-target species and reduced costs when compared to traditional invasive species removal techniques. Given the risks of such an approach described below, the GBIRd partnership is committed to a deliberate, step-wise process that will only proceed with public alignment, as recommended by the world's leading gene drive researchers from the Australian and US National Academy of
Sciences and many others. A wider Outreach Network for Gene Drive Research exists to raise awareness of the value of gene drive research for the public good.
Some scientists are concerned about the technique, fearing it could spread and wipe out species in native habitats. The gene could mutate, potentially causing unforeseen problems. 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.

Predator Free 2050

The Predator Free 2050 project is a New Zealand government program to completely eliminate eight invasive mammalian predator species from the country by 2050. The projects was first announced in 2016 by New Zealand's prime minister John Key and in January 2017 it was announced that gene drives would be used in the effort. In 2017 one group in Australia and another in Texas released preliminary research into creating 'daughterless mice', using gene drives in mammals.

California

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.

Wild animal welfare

The transhumanist philosopher David Pearce has advocated for using CRISPR-based gene drives to reduce the suffering of wild animals. Kevin M. Esvelt, an American biologist who has helped develop gene drive technology, has argued that there is a moral case for the elimination of the New World screwworm through such technologies because of the immense suffering that infested wild animals experience when they are eaten alive.