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.
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.
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 (storms, floods, etc.), 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%.
- 1 Mechanism
- 2 Technical limitations
- 3 Issues
- 4 History
- 5 Control strategies
- 6 CRISPR
- 7 Applications
- 8 See also
- 9 References
- 10 External links
In sexually-reproducing species, most genes are present in two copies (which can be the same or different alleles), 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.
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) 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).
Spreading in the population
This section needs additional citations for verification. (November 2017) (Learn how and when to remove this template message)
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 (≈90%), 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.
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.
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 highlighted by researchers include:
- 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.
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.
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.
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 (WHO) 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.
Target Malaria, 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.
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. As of 2014[update], 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.
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.
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 claimed that by applying the technique to 1% of the wild population of mosquitoes, 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 (GBIRd) 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 (as could any gene). 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 (including rats, short-tailed weasels, and possums) 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.
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.
- Biological machines
- Meiotic drive
- Genome editing
- Population control
- Sterile insect technique
- Synthetic biology
- Target Malaria
- Callaway, Ewen (21 July 2017). "US defence agencies grapple with gene drives". Nature. Retrieved 2018-04-24.
- Champer, Jackson; Buchman, Anna; Akbari, Omar S. (March 2016). "Cheating evolution: engineering gene drives to manipulate the fate of wild populations". Nature Reviews Genetics. 17 (3): 146–159. doi:10.1038/nrg.2015.34. ISSN 1471-0056. PMID 26875679.
- Esvelt, Kevin M; Smidler, Andrea L; Catteruccia, Flaminia; Church, George M (July 2014). "Concerning RNA-guided gene drives for the alteration of wild populations". eLife. 3: e03401. doi:10.7554/eLife.03401. PMC 4117217. PMID 25035423.
- Burt, A. (2003). "Site-specific selfish genes as tools for the control and genetic engineering of natural populations". Proceedings of the Royal Society B: Biological Sciences. 270 (1518): 921–928. doi:10.1098/rspb.2002.2319. PMC 1691325. PMID 12803906.
- "U.S. researchers call for greater oversight of powerful genetic technology | Science/AAAS | News". News.sciencemag.org. Retrieved 2014-07-18.
- Benedict, M.; D'Abbs, P.; Dobson, S.; Gottlieb, M.; Harrington, L.; Higgs, S.; James, A.; James, S.; Knols, B.; Lavery, J.; O'Neill, S.; Scott, T.; Takken, W.; Toure., Y. (April 2008). "Guidance for contained field trials of vector mosquitoes engineered to contain a gene drive system: Recommendations of a scientific working group". Vector Borne and Zoonotic Diseases (Larchmont, N.Y.). 8 (2): 127–66. doi:10.1089/vbz.2007.0273. PMID 18452399.
- "This Gene-Editing Tech Might Be Too Dangerous To Unleash". Wired.
- Champer, Jackson; Buchman, Anna; Akbari, Omar S. (2016). "Cheating evolution: engineering gene drives to manipulate the fate of wild populations". Nature Reviews Genetics. 17 (3): 146–159. doi:10.1038/nrg.2015.34. PMID 26875679.
- "Even CRISPR". The Economist. ISSN 0013-0613. Retrieved 2016-05-03.
- Unckless, Robert L.; Messer, Philipp W.; Connallon, Tim; Clark, Andrew G. (2015-10-01). "Modeling the Manipulation of Natural Populations by the Mutagenic Chain Reaction". Genetics. 201 (2): 425–431. doi:10.1534/genetics.115.177592. ISSN 0016-6731. PMC 4596658. PMID 26232409.
- Bull, James J. (2016-04-02). "Lethal Gene Drive Selects Escape through Inbreeding". bioRxiv 046847.
- Oye, Kenneth A.; Esvelt, Kevin; Appleton, Evan; Catteruccia, Flaminia; Church, George; Kuiken, Todd; Lightfoot, Shlomiya Bar-Yam; McNamara, Julie; Smidler, Andrea (2014-08-08). "Regulating gene drives". Science. 345 (6197): 626–628. doi:10.1126/science.1254287. ISSN 0036-8075. PMID 25035410.
- Drinkwater, Kelly; Kuiken, Todd; Lightfoot, Shlomiya; McNamara, Julie; Oye, Kenneth. "CREATING A RESEARCH AGENDA FOR THE ECOLOGICAL IMPLICATIONS OF SYNTHETIC BIOLOGY" (PDF). The Wilson Center and the Massachusetts Institute of Technology Program on Emerging Technologies. Archived from the original (PDF) on 2014-07-30. Retrieved 2014-07-20.
- Regalado, Antonio (December 12, 2017). "California farmers are eyeing a controversial genetic tool to eliminate fruit flies". MIT Technology Review. Retrieved 2018-04-28.
- "Genetically Engineering Almost Anything". PBS. 17 July 2014. "I don't care if it's a weed or a blight, people still are going to say this is way too massive a genetic engineering project," [bioethicist] Caplan says. "Secondly, it's altering things that are inherited, and that's always been a bright line for genetic engineering."
- Wade, Nicholas (3 December 2015). "Scientists Place Moratorium on Edits to Human Genome That Could Be Inherited". The New York Times. Retrieved 3 December 2015.
- Huffaker, Sandy (9 December 2015). "Geneticists vote to allow gene editing of human embryos". New Scientist. Retrieved 18 March 2016.
- Gallagher, James (1 February 2016). "Scientists get 'gene editing' go-ahead". BBC News. Retrieved 1 February 2016.
- Cheng, Maria (1 February 2016). "Britain approves controversial gene-editing technique". Associated Press. Archived from the original on 1 February 2016. Retrieved 1 February 2016.
- "Gene Drive Research in Non-Human Organisms: Recommendations for Responsible Conduct". National Academies of Sciences, Engineering, and Medicine. June 8, 2016. Retrieved June 9, 2016.
- Noble, Charleston; Adlam, Ben; Church, George; Esvelt, Kevin; Nowak, Martin. "Current CRISPR gene drive systems are likely to be highly invasive in wild populations". biorxiv.org. Retrieved 13 December 2017.
- Esvelt, Kevin; Gemmell, Neil (2017). "Conservation demands safe gene drive". PLOS Biology. 15 (11): e2003850. doi:10.1371/journal.pbio.2003850. PMC 5689824. PMID 29145398.
- Yong, Ed. "One Man's Plan to Make Sure Gene Editing Doesn't Go Haywire". theatlantic.com. Retrieved 13 December 2017.
- Zimmer, Carl (2017-11-16). "'Gene Drives' Are Too Risky for Field Trials, Scientists Say". The New York Times. ISSN 0362-4331. Retrieved 2018-04-22.
- Windbichler, N.; Menichelli, M.; Papathanos, P. A.; Thyme, S. B.; Li, H.; Ulge, U. Y.; Hovde, B. T.; Baker, D.; Monnat Jr, R. J.; Burt, A.; Crisanti, A. (2011). "A synthetic homing endonuclease-based gene drive system in the human malaria mosquito". Nature. 473 (7346): 212–215. doi:10.1038/nature09937. PMC 3093433. PMID 21508956.
- Chan, Y.-S. (2011). "Insect Population Control by Homing Endonuclease-Based Gene Drive: An Evaluation in Drosophila melanogaster". Genetics. 188 (1): 33–44. doi:10.1534/genetics.111.127506. PMC 3120159. PMID 21368273.
- Chan, Yuk-Sang (2013). "Optimising Homing Endonuclease Gene Drive Performance in a Semi-Refractory Species: The Drosophila melanogaster Experience". PLoS ONE. 8 (1): e54130. doi:10.1371/journal.pone.0054130. PMC 3548849. PMID 23349805.
- "TDR | About us". Who.int. Retrieved 2014-07-18.
- "TDR | A new framework for evaluating genetically modified mosquitoes". Who.int. 2014-06-26. Retrieved 2014-07-18.
- "EFSA - Guidance of the GMO Panel: Guidance Document on the ERA of GM animals". EFSA Journal. 11 (5): 3200. 2013. doi:10.2903/j.efsa.2013.3200. Retrieved 2014-07-18.
- Regalado, Antonio. "Bill Gates doubles his bet on wiping out mosquitoes with gene editing". Retrieved 2016-09-20.
- Neslen, Arthur (2017-12-04). "US military agency invests $100m in genetic extinction technologies". The Guardian. ISSN 0261-3077. Retrieved 2017-12-04.
- Regalado, Antonio (10 February 2017). "First Gene Drive in Mammals Could Aid Vast New Zealand Eradication Plan". MIT Tech Review. Retrieved 14 February 2017.
- Elizabeth Pennisi (2013-08-23). "The CRISPR Craze". Sciencemag.org. Retrieved 2014-07-18.
- Pollack, Andrew (May 11, 2015). "Jennifer Doudna, a Pioneer Who Helped Simplify Genome Editing". New York Times. Retrieved May 12, 2015.
- Dicarlo, J. E.; Chavez, A.; Dietz, S. L.; Esvelt, K. M.; Church, G. M. (2015). "RNA-guided gene drives can efficiently and reversibly bias inheritance in wild yeast". bioRxiv 013896.
- Gantz, V. M.; Bier, E. (2015). "The mutagenic chain reaction: A method for converting heterozygous to homozygous mutations". Science. 348 (6233): 442–444. doi:10.1126/science.aaa5945. PMC 4687737. PMID 25908821.
- Gantz, Valentino M.; Jasinskiene, Nijole; Tatarenkova, Olga; Fazekas, Aniko; Macias, Vanessa M.; Bier, Ethan; James, Anthony A. (2015-12-08). "Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi". Proceedings of the National Academy of Sciences. 112 (49): E6736–E6743. doi:10.1073/pnas.1521077112. ISSN 0027-8424. PMC 4679060. PMID 26598698.
- Hammond, Andrew; Galizi, Roberto; Kyrou, Kyros; Simoni, Alekos; Siniscalchi, Carla; Katsanos, Dimitris; Gribble, Matthew; Baker, Dean; Marois, Eric (2015-12-07). "A CRISPR-Cas9 gene drive system targeting female reproduction in the malaria mosquito vector Anopheles gambiae". Nature Biotechnology. 34 (1): 78–83. doi:10.1038/nbt.3439. ISSN 1546-1696. PMC 4913862. PMID 26641531.
- DiCarlo, James; Chavez, Alejandro; Dietz, Sven; Esvelt, Kevin; Church, George (16 November 2015). "Safeguarding CRISPR-Cas9 gene drives in yeast". Nature Biotechnology. 33 (12): 1250–1255. doi:10.1038/nbt.3412. PMC 4675690. PMID 26571100.
- on YouTube
- Kalmakoff, James (11 October 2016). "CRISPR for pest-free NZ". Retrieved 19 October 2016.
- "GBIRd Fact Sheet" (PDF). 1 April 2018. Retrieved 14 November 2018.
- "Mission & Principles Statement". 1 July 2018. Retrieved 14 November 2018.
- "'Gene drives' could wipe out whole populations of pests in one fell swoop". THE CONVERSATION.
- "An Argument Against Gene Drives to Extinguish New Zealand Mammals: Life Finds a Way". Plos blogs.
- Campbell, Colin (17 October 2016). "Risks may accompany gene drive technology". Otago Daily Times. Retrieved 19 October 2016.
- Stockton, Nick (July 27, 2016). "How New Zealand Plans to Kill Its (Non-Human) Invasive Mammals". WIRED.
- "Predator Free NZ - Expert Q&A". Scoop. 17 January 2017. Retrieved 17 January 2017.
- The Outreach Network for Gene Drive Research website
- The Genetic Biocontrol of Invasive Rodents (GBIRd) program website
- Esvelt, Kevin. "Gene Drives for the Alteration of Wild Populations". Retrieved 11 August 2014.
- "Gene Drive from Harvard's Wyss Institute". Wyss Institute. 2014-07-17. Retrieved 2014-08-11.
- De Chant, Tim (July 17, 2014). "Genetically Engineering Almost Anything". NOVA. Retrieved 11 August 2014.
- Johnson, Carolyn (July 17, 2014). "Harvard scientists want gene-manipulation debate". National Geographic. Retrieved 11 August 2014.
- Langin, Katie (July 17, 2014). "Genetic Engineering to the Rescue Against Invasive Species?". National Geographic. Retrieved 11 August 2014.
- Zimmer, Carl (July 17, 2014). "A Call to Fight Malaria One Mosquito at a Time by Altering DNA". The New York Times. Retrieved 20 July 2014.
- "The age of the red pen". The Economist. August 22, 2015. ISSN 0013-0613. Retrieved 2015-08-25.
- "The most selfish genes". The Economist. August 22, 2015. ISSN 0013-0613. Retrieved 2015-08-25.
- Noble, Charleston; Adlam, Ben; Church, George M.; Esvelt, Kevin M.; Nowak, Martin A. (2017-11-16). "Current CRISPR gene drive systems are likely to be highly invasive in wild populations". bioRxiv: 219022. doi:10.1101/219022.
- Esvelt, Kevin M.; Gemmell, Neil J. (2017-11-16). "Conservation demands safe gene drive". PLOS Biology. 15 (11): e2003850. doi:10.1371/journal.pbio.2003850. ISSN 1545-7885.