Malaria remains one of the deadliest diseases in the world. Every year, malaria infections cause hundreds of thousands of deaths, with the majority of deaths affecting children under the age of five. The Centers for Disease Control and Prevention recently announced that five cases of mosquito-borne malaria have been detected in the United States, the first reported spread in the country in two decades.
Fortunately, scientists are developing safe technologies to stop malaria transmission by genetically modifying the mosquitoes that spread the parasite that causes the disease. Researchers at the University of California, San Diego, led by the laboratory of Professor Omar Akbari, have developed a new way to genetically suppress populations of Anopheles gambiae, mosquitoes that primarily spread malaria in Africa and contribute to economic poverty in affected regions. The new system targets and kills females in the A. gambiae population because they bite and spread the disease.
Publication on July 5 in the magazine Scientists progress, first author Andrea Smidler, a postdoctoral researcher in the School of Biological Sciences at UC San Diego, along with former master’s students and co-first authors James Pai and Reema Apte, created a system called Ifegenia, a acronym for “hereditary elimination of females by genetically encoded nucleases to interrupt alleles.” The technique leverages CRISPR technology to disrupt a gene known as femaleless (flee) which controls sexual development in A. gambiae mosquitoes.
Scientists from UC Berkeley and the California Institute of Technology contributed to the research effort.
Ifegenia works by genetically encoding the two main elements of CRISPR in African mosquitoes. These include a Cas9 nuclease, the molecular “scissors” that make the cuts, and a guide RNA that directs the system to the target using a technique developed in these mosquitoes in Akbari’s lab. They genetically engineered two families of mosquitoes to separately express Cas9 and flee-targeting of guide RNA.
“We crossed them together and in the offspring it killed all the female mosquitoes,” Smidler said, “it was extraordinary.” In the meantime, A. gambiae male mosquitoes inherit Ifegenia but the genetic modification has no impact on their reproduction. They remain able to reproduce and propagate Ifegenia. The spread of the parasite is ultimately stopped as the females are removed and the population reaches a reproductive dead end. The new system, the authors note, circumvents some barriers to genetic resistance and control problems encountered by other systems such as gene drives, since the Cas9 components and guide RNA are kept separate until the population is ready to be deleted.
“We show that Ifegenia males remain reproductively viable and can charge at both flee mutations and CRISPR machinery to induce flee mutations in subsequent generations, leading to sustained population suppression,” the authors note in the paper. “Through modeling, we demonstrate that iterative releases of non-biting Ifegenia males can act as a system of suppression and effective, confineable, controllable and safe population elimination. “.
Traditional methods of combating the spread of malaria, such as bed nets and insecticides, are increasingly proving ineffective in stopping the spread of the disease. Insecticides are still widely used around the world, primarily in an effort to stop malaria, which increases health and ecological risks in parts of Africa and Asia.
Smidler, who earned a doctorate (public health biological sciences) from Harvard University before joining UC San Diego in 2019, applies his expertise in developing genetic technologies to combat the spread of disease and resulting economic damage. Once she and her colleagues developed Ifegenia, she was surprised by how effective the technology was as a suppression system.
“This technology has the potential to be the safe, controllable and scalable solution the world urgently needs to eliminate malaria once and for all,” said Akbari, a professor in the Department of Cellular and Developmental Biology. “We must now direct our efforts toward social acceptance, regulatory use authorizations and funding opportunities to put this system to the ultimate test of suppressing malaria-transmitting wild mosquito populations. We are on the verge of ‘have a major impact in the world and will not stop until this goal is achieved.
The researchers note that the technology behind Ifegenia could be adapted to other species that spread deadly diseases, such as mosquitoes known to transmit dengue (fracture fever), chikungunya and yellow fever viruses.
The full list of authors includes Andrea Smidler, James Pai, Reema Apte, Hector Sanchez C., Rodrigo Corder, Eileen Jeffrey Gutierrez, Neha Thakre, Igor Antoshechkin, John Marshall and Omar Akbari.