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    Emergence of resistant organisms impede gene drives success in the wild

    Adult female mosquitoes modified by gene drives to be infertile.

    Researchers are experimenting an emerging genetic-engineering technology called gene drives on mosquitoes in the small city of Terni in central Italy, as part of a multimillion-dollar project called Target Malaria. The mosquito cages, each occupying 150 cubic metres, simulate the muggy habitats in which Africa’s Anopheles gambiae mosquitoes thrive. By studying the insects under more-natural conditions, scientists hope to better understand how to eradicate them, and in turn malaria.

    Gene drives thwart the rules of inheritance in sexually reproducing organisms. Normally, offspring have a 50:50 chance of inheriting a gene from their parents. Gene drives preferentially passing on one version to an organism’s offspring until, in theory, an entire population bears that gene. The technique can quickly disseminate genetic modifications in wild populations through an organism’s offspring, prompting some activists to call for it to be shelved.

    Yet recent research has indicated that gene drives might not be as effective as activists think, as a major hurdle to using them to eliminate diseases and vanquish invasive pests has been identified: evolution. Although organisms altered by gene drives, including mosquitoes, have shown promise in proof-of-concept laboratory experiments, wild populations will almost certainly develop resistance to the modifications. Researchers have begun identifying how this occurs so that they can address the problem.

    Interest in gene drives has surged with the advent of CRISPR–Cas9 gene editing, which can be used to copy a mutation from one chromosome into another. In late 2015, researchers reported a CRISPR gene drive that caused an infertility mutation in female mosquitoes to be passed on to all their offspring. Lab experiments showed that the mutation increased in frequency as expected over several generations, but resistance to the gene drive also emerged, preventing some mosquitoes from inheriting the modified genome.

    Philipp Messer, a population geneticist at Cornell University explained that just as antibiotics enable the rise of drug-resistant bacteria, population-suppressing gene drives create the ideal conditions for resistant organisms to flourish. One source of this resistance is the CRISPR system itself as occasionally cells sew the incision back together after Cas9 cuts and inserts/deletes random DNA letters, which results in a sequence that the CRISPR gene-drive system no longer recognizes, halting the spread of the modified code. The researchers in Italy have found this form of resistance in some mosquitoes. And Messer’s team reported in December that these mutants are likely to flourish.

    Natural genetic variation is another route to resistance. CRISPR-based gene drives work by recognizing short genetic sequences, and individuals with differences at these sites would be immune to the drive. A recent study analysed the genomes of 765 wild Anophelesmosquitoes from across Africa and found extreme genetic diversity, which would limit the list of potential gene-drive targets.

    The Target Malaria team has developed a second generation of gene-drive mosquitoes, hoping to slow the development of resistance, says Andrea Crisanti, a molecular parasitologist at Imperial College London. The researchers plan to test them in their new Italian facility later this year to get a sense of how the mosquitoes might fare in the wild. But molecular biologist Tony Nolan, also at Imperial, expects evolution to throw up some surprises. He says that his greatest worry about gene drives is that they simply won’t work.

    Read More:

    1. Nature 542, 15 (2016). doi:10.1038/542015a

    2. Hammond, A. et al. Nature Biotechnol. 34, 78–83 (2016). doi:10.1038/nbt.3439

    3. Unckless, R. L., Clark, A. G. & Messer, P. W. Genetics (2016).

    4. Miles, A. et al. Preprint at bioRxiv (2016).

    5. Drury, D., Siniard, D. J., Zentner, G. E. & Wade, M. J. Preprint at bioRxiv (2016)