Creative Minds: Building a CRISPR Gene Drive Against Malaria

Valentino Gantz

Valentino Gantz/Credit: Erik Jepsen

Researchers have used Drosophila melanogaster, the common fruit fly that sometimes hovers around kitchens, to make seminal discoveries involving genetics, the nervous system, and behavior, just to name a few. Could a new life-saving approach to prevent malaria be next? Valentino Gantz, a researcher at the University of California, San Diego, is on a path to answer that question.

Gantz has received a 2016 NIH Director’s Early Independence Award to use Drosophila to hone a new bioengineered tool that acts as a so-called “gene drive,” which spreads a new genetically encoded trait through a population much faster than would otherwise be possible. The lessons learned while working with flies will ultimately be applied to developing a more foolproof system for use in mosquitoes with the hope of stopping the transmission of malaria and potentially other serious mosquito-borne diseases.

Interest in building a gene drive in the laboratory has been around since the late 1960s. It involves constructing a gene that integrates into the DNA of a troublesome insect or plant and then propagates itself, spreading its encoded trait through a population in a few generations, or much faster than normal Mendelian inheritance.

Gene drives were largely theoretical until the recent arrival of highly precise gene editing tools like CRISPR/Cas9.  This amazing bacterial system, which has been adapted to virtually all species (including insects and humans), makes it possible to find the right place in the genome to insert the gene drive and start the propagation process.

About three years ago, as others reported early progress with CRISPR/Cas9-homing gene drives in a single-celled yeast species, Gantz was a busy Ph.D. student studying Drosophila development in the lab of UCSD scientist Ethan Bier. Not even thinking about malaria or human health, Gantz wondered whether CRISPR/Cas9 could help him find more success in passing along traits of interest in his studies.

Gantz took a copy of the recessive yellow gene, which affects a fruit fly’s color, and inserted CRISPR/Cas9 in the middle. His plan was this three-part construct, or cassette, would integrate reliably in the genomes of fruit flies without the cell’s own DNA copy editors cutting it out.

But getting a single copy into the genome wouldn’t be enough to turn the flies yellow. That’s where the self-replicating gene drive comes in. When those flies breed, the activated cassette in the developing offspring would cut the opposing chromosome and copy itself into that DNA too. This would give the flies two copies of the yellow gene drive, making this color dominant. Thus, the success or failure of the experiment would be easy to see: the next generation of flies should all be yellow.

The experiment worked on the first try; 97 percent of the next generation was yellow. It was proof of principle that Gantz’s gene drive was viable, making it the first gene drive to work in a multicellular organism [1 – 3].

Bier shared the news with a colleague interested in developing a gene drive to make mosquitoes resistant to malaria. The phone call led to a collaboration that successfully spread a malaria-resistance gene in a laboratory population of Anopheles stephensi mosquitoes, a primary carrier of the parasites that cause malaria. The gene drive forced the mosquitoes to make two antibodies against malaria parasites.

Now, with his Early Independence Award, Gantz is taking a closer look at his gene drive. He wants to learn precisely how the system works, understanding in fine detail the process by which the cassettes copy themselves into chromosomes. When the system fails, he wants to learn where problems occur and how to fix them.

A major question is whether gene drives will work in the wild over the long term. It’s possible that mosquitoes could become resistant to incorporating the cassette or the malaria parasite will mutate and circumvent the effects of the gene drive.

As a possible solution, Gantz will study incorporating several different gene drives at once into a single insect. He also will study the possibility that the CRISPR/Cas9 technology could create unintended edits in other parts of the genome, potentially making the engineered mosquitoes at a disadvantage in the wild.

Because of the ability of gene drives to propagate rapidly through a species with consequences that are not yet completely understood, all of these experiments are carried out using a high level of biological containment. None of the engineered insects are allowed to escape.

If all goes well, gene drives hold tremendous promise to help control mosquito-borne diseases like malaria, which killed an estimated 430,000 people worldwide in 2015. But there are also many questions to consider about their potential ecological impact, which will be critical in weighing the risks and benefits of their possible use. As part of that equation, more research to learn how to optimize and control these potentially powerful tools is essential.

Reference:

[1] Genome editing. The mutagenic chain reaction: a method for converting heterozygous to homozygous mutations. Gantz VM, Bier E. Science. 2015 Apr 24;348(6233):442-444.

[2] Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi. Gantz VM, Jasinskiene N, Tatarenkova O, Fazekas A, Macias VM, Bier E, James AA. Proc Natl Acad Sci U S A. 2015 Dec 8;112(49):E6736-43.

[3] The dawn of active genetics. Gantz VM, Bier E. Bioessays. 2016 Jan;38(1):50-63

Links:

Gantz Lab (University of California, San Diego)

Gantz Project Information (NIH RePORTER)

NIH Director’s Early Independence Award (Common Fund)

NIH Support: Common Fund

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