Gene drive

Gene drive is the practice of "stimulating biased inheritance of particular genes to alter entire populations."[1] It has been proposed as a technique for changing wild populations of harmful organisms such as mosquitoes to be less dangerous. In addition to combating diseases spread by insects, gene drives might be used to control invasive species or to eliminate herbicide- or pesticide resistance.[1][2][3] Possible alterations include adding, disrupting, or modifying genes, including some that reduce reproductive capacity and may cause a population crash.[2][4] Synthetic gene drives based on homing endonucleases[4] were first proposed in 2003.

History

Austin Burt, an evolutionary geneticist at Imperial College London,[5] first outlined the possibility of building gene drives based on natural "selfish" homing endonuclease genes.[4] Researchers had already shown that these “selfish” genes could spread rapidly through successive generations. Burt suggested that gene drives might be used to prevent a mosquito population from transmitting the malaria parasite or crash a mosquito population. Gene drives based on homing endonucleases have been demonstrated in the laboratory in transgenic populations of mosquitoes[6] and fruit flies.[7][8] These enzymes could be used to drive alterations through wild populations.[1]

CRISPR/Cas9

CRISPR/Cas9[9] is a DNA cutting method that has made genetic engineering faster, easier, and more efficient since 2013.[10] The approach involves expressing the RNA-guided Cas9 endonuclease along with guide RNAs directing it to a particular sequence to be edited. When Cas9 cuts the target sequence, the cell often repairs the damage by replacing the original sequence with homologous DNA. Making a guide RNA to direct Cas9 to cut any specific gene is straightforward, the target gRNA sequence is introduced into a CRISPR-positive cell and then the CRISPR-cas complex can be isolated via several protein isolation techniques.[11] CRISPR tremendously simplifies the process of deleting, adding, or modifying genes. As of 2014, it had successfully been tested in cells of 20 species, including humans.[2] In many of these species, the edits modified their germline, allowing them to be inherited.

Esvelt and coworkers first suggested that CRISPR/Cas9 might be used to build endonuclease gene drives.[2] This could be accomplished by encoding the Cas9 gene and guide RNAs used for genome editing adjacent to the altered gene, causing the editing event to re-occur in each organism that inherits one copy of the modification and one copy of the wild-type gene. Because of CRISPR/Cas9's targeting flexibility, RNA-guided gene drives could theoretically be used to spread 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.

Population-level genome changes could be reversed or blocked using the same technique, as a safeguard.[2] CRISPR/Cas9 could also permit a variety of gene drive architectures intended to control rather than crash populations.

In 2015 researchers successfully tested CRISPR-based gene drives in Saccharomyces[12], Drosophila[13] and mosquitoes.[14][15] All four studies demonstrated extremely efficient inheritance distortion over successive generations, with one study demonstrating the spread of a gene drive into naïve laboratory populations.[15] Drive-resistant alleles are expected to arise for each of the described gene drives, however this can be delayed or prevented by targeting highly conserved sites at which resistance is expected to have a severe fitness cost.

In December 2015, scientists of major world academies called for a moratorium on inheritable human genome edits that would lead to pregnancies, 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]

Mechanism

Some genes in species that reproduce sexually have greater than the normal 50% chance of being inherited. This allows them to spread through a population even if they reduce the fitness of each individual organism. By similarly biasing the inheritance of particular altered genes, gene drives might be used to spread alterations through wild populations.[2][4]

Endonuclease gene drives work by cutting the corresponding locus of chromosomes that do 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. If the cell is a germline cell, the modification will carry to offspring.

A gene drive typically requires dozens of generations to affect a substantial fraction of a population because it can never more than double in frequency with each generation. Alternatively, releasing drive-containing organisms in sufficient numbers can affect the rest within a couple of generations. The process may require under a year for some invertebrates, but centuries for organisms with years-long intervals between birth and sexual maturity, such as humans.[20]

Types

Issues

Issues that researchers have highlighted include:[21]

There are bioethics concerns as well, as the gene drive is a very powerful tool.[22]

Applications

One possible application is to genetically modify mosquitoes and other disease vectors so they cannot transmit diseases such as malaria and dengue fever. In June 2014, the World Health Organization (WHO) Special Programme for Research and Training in Tropical Diseases[23] issued guidelines [24] for evaluating genetically modified mosquitoes. In 2013 the European Food Safety Authority issued a protocol[25] for environmental assessments of all genetically modified organisms.

See also

References

  1. 1 2 3 4 "U.S. researchers call for greater oversight of powerful genetic technology | Science/AAAS | News". News.sciencemag.org. Retrieved 2014-07-18.
  2. 1 2 3 4 5 6 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. PMID 25035423.
  3. ↑ 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). "Vector-Borne and Zoonotic Diseases". Vector-Borne and Zoonotic Diseases 8 (2): 127–166. doi:10.1089/vbz.2007.0273. PMID 18452399.
  4. 1 2 3 4 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.
  5. ↑ Austin Burt profile
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ Elizabeth Pennisi (2013-08-23). "The CRISPR Craze". Sciencemag.org. Retrieved 2014-07-18.
  10. ↑ Pollack, Andrew (May 11, 2015). "Jennifer Doudna, a Pioneer Who Helped Simplify Genome Editing". New York Times. Retrieved May 12, 2015.
  11. ↑ Cong, Le; Ran, Ann; Cox, David; Lin, Shuailiang; Barretto, Robert; Habib, Naomi; Hsu, Patrick; Wu, Xuebing; Jiang, Wenyen; Marraffini, Luciano; Zhang, Feng (15 February 2013). "Multiplex Genome Engineering Using CRISPR/Cas Systems". Science 339 (6121): 819–823. doi:10.1126/science.1231143. PMC: 3795411. PMID 23287718.
  12. ↑ 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". doi:10.1101/013896.
  13. ↑ Gantz, V. M.; Bier, E. (2015). "The mutagenic chain reaction: A method for converting heterozygous to homozygous mutations". Science 348: 442–444. doi:10.1126/science.aaa5945.
  14. ↑ 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. PMID 26598698.
  15. 1 2 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. advance online publication. doi:10.1038/nbt.3439. ISSN 1546-1696.
  16. ↑ Wade, Nicholas (3 December 2015). "Scientists Place Moratorium on Edits to Human Genome That Could Be Inherited". New York Times. Retrieved 3 December 2015.
  17. ↑ Huffaker, Sandy (9 December 2015). "Geneticists vote to allow gene editing of human embryos". New Scientist. Retrieved 18 March 2016.
  18. ↑ Gallagher, James (1 February 2016). "Scientists get 'gene editing' go-ahead". BBC News (BBC). Retrieved 1 February 2016.
  19. ↑ Cheng, Maria (1 February 2016). "Britain approves controversial gene-editing technique". AP News. Retrieved 1 February 2016.
  20. ↑ Oye, Kenneth A.; Esvelt, Kevin; Appleton, Evan; Catterucci, Flaminia; Church, George; Kuiken, Todd; Bar-Yam Lightfoot, Shlomiya; McNamara, Julie; Smidler, Andrea; Collins, James P. (17 July 2014). "Regulating gene drives". Science 345: 626–628. doi:10.1126/science.1254287.
  21. ↑ 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.
  22. ↑ "Genetically Engineering Almost Anything". PBS. 17 Jul 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.”
  23. ↑ "TDR | About us". Who.int. Retrieved 2014-07-18.
  24. ↑ "TDR | A new framework for evaluating genetically modified mosquitoes". Who.int. 2014-06-26. Retrieved 2014-07-18.
  25. ↑ "EFSA - Guidance of the GMO Panel: Guidance Document on the ERA of GM animals". Efsa.europa.eu. doi:10.2903/j.efsa.2013.3200. Retrieved 2014-07-18.

External links

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