Genetic Engineering & Biotechnology News

SEP15 2017

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14 | SEPTEMBER 15, 2017 | GENengnews.com | Genetic Engineering & Biotechnology News lar concern in gene-drive studies revolves around the acci- dental escape from the laboratory of even a single organism, and the subsequent consequences over time on wild popula- tions. "Because fruit flies are present outside of every labora- tory, escape is easier in this model," warns Dr. Church. Dr. Church and colleagues recently developed and vali- dated two molecular confinement methods. One method encodes Cas9 on an unlinked episomal plasmid and ensures that the gene drive element contains only the single guide RNA. (In this arrangement, the single-guide RNA-only gene drive is unable to spread in wild organisms, which lack Cas9.) The other method involves using exclusively synthet- ic target sequences, which are not encountered in wild-type organisms. As part of these studies, Dr. Church's laboratory illustrat- ed the benefits of testing CRISPR/Cas9-based gene drives in the budding yeast before conducting work on multicellular organisms. Additional work with mathematical models led Dr. Church and colleagues to propose the use of alternative designs that could select against resistant alleles and improve the gene drive's evolutionary stability. One of the technical challenges in engineering mosquitoes is the need to perform the engineering within or near essential genes. "Engineering genes that are not important to the organism will quickly eliminate the gene drive because the organism does not need the target site," explains Dr. Church. Engineering Parasite-Resistant Mosquitoes "As part of our efforts focusing on malaria, we are trying to create tools and generate mos- quitoes that could be used for rigorous tests in- cluding large cage trials and subsequently, if the regulatory approvals are given, for field trials," says Ethan Bier, Ph.D., professor of cell and de- velopmental biology at the University of Califor- nia, San Diego. Dr. Bier's group was the first to show that a gene drive can be created in the fruit fly. Overall, two competing strategies have been envisioned and developed for using gene-drive technologies. One strate- gy involves the use of mosquitoes to distribute or disseminate an immunizing gene cassette. If this strategy is implemented correctly, notes Dr. Bier, it would not have much or any im- pact on the health or fitness of the mosquitoes. The other strategy involves using gene drive to sterilize or reduce the population of mosquitoes. According to Dr. Bier, this is a ver- sion of genetic insecticide. Dr. Bier's laboratory is pursuing the first strategy in col- laboration with a team of scientists based at the University of California, Irvine, and led by Anthony James, Ph.D., a pro- fessor of microbiology and molecular genetics, and of molec- ular biology and biochemistry. The collaboration is focusing on population-level mosquito modifications in which genes that confer a parasite-resistant phenotype are engineered into the mosquitoes that transmit the pathogen. "The immunizing cassette, originally developed by Dr. James' laboratory, would just stay in the population and not be subject to evolutionary pressures that try to rid those mosquitoes from the environment," explains Dr. Bier. "They might therefore be present long enough to have a significant impact on the prevalence of the malaria parasite by blocking its transmission." In a recent study using Anopheles stephensi, a malaria vector on the Indian subcontinent, Dr. Bier and colleagues in the Dr. James' group revealed that CRISPR/Cas9-direct- ed homologous recombination drives gene conversion at a more than 99.5% efficiency in mosquito transgene heterozy- gotes. The technology to perform this work is based on the mutagenic chain reaction, which Dr. Bier and colleagues pre- viously developed in Drosophila melanogaster, and in which a heterozygous mutation is converted to a homologous loss- of-function mutation in germline and somatic cells. Gene-drive technologies have applications for other vec- tor-borne diseases, such as leishmaniasis and Chagas disease, as well as for population reduction schemes to control crop pests. "Any scheme that goes after reducing the population of any insect or organism in the wild, even though it may be successful, will at the end, always be an uphill battle," OMICS Feature Gene Drives Steer toward Road Tests Continued from page 1 caption " The regulatory agencies are still coming to grips with what it means to have a technology that will be used in an environment that is beyond a contain- ment barrier." — Dr. Adelman Molecular mechanism of gene drive. Thomas Julou/Wikipedia Commons

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