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Gene drives get a precision upgrade

April 16, 2019

undefinedEthan Bier, Ph.D., talks about his recent gene editing research at the 2018 Allen Frontiers Symposium at the Allen Institute.

Gene drives, a method to “drive” a new gene through a population in a way that bypasses the natural order of inheritance, were first developed around five years ago. Researchers hope the technique could one day be used to eliminate deadly diseases like malaria or to manage pests that spread illness or decimate crops, although no gene drives have yet been deployed in the wild. 

In their current incarnation, gene drives are a relatively blunt tool. They can deliver an entire new gene to a living creature, but they can’t fine tune the organism’s existing DNA. Now, gene drives are getting an upgrade. 

In a new twist on the technique, researchers at the University of California San Diego developed a gene drive that makes very precise and subtle changes in the DNA, changes that can still sweep through a population and which could have even broader applications for zoonotic diseases (diseases that spread from other animals to us, like malaria or Lyme disease) or agriculture. They’ve recently published a study describing the new method in the journal Nature Communications. 

If you think of the genome like a book and the gene drive as an editor, the previous incarnations “are like bringing in whole sentences or paragraphs to make a change,” said Ethan Bier, Ph.D., an Allen Distinguished Investigator and lead author on the study, which demonstrated the technique in fruit flies in the lab. “This new advance offers the ability to edit single letters.” 

There’s a lot you can do with whole sentences of DNA — work is already under way in several laboratories to introduce new genes into mosquito populations that could wipe out malaria. But there’s even more you can do with the ability to make subtle tweaks via a gene drive, Bier said. Like engineering renewed sensitivity to pesticides into insects with acquired resistance to those chemicals that destroy crops, which would mean farmers would have to use far lower amounts of pesticides every year, potentially reducing collateral damage to other, beneficial insect species like bees. Or introducing drought-hardiness into wheat, which has six copies of every gene instead of two and thus is very difficult to engineer using standard gene editing approaches.

Subtle changes

Gene drives, which Bier has helped spearhead, combine two concepts that exist separately in nature: CRISPR, a bacteria-derived gene-editing technique, and “selfish genes,” genes that perpetuate their own spread throughout a species at greater frequencies than genes that are normally inherited. A typical gene drive couples the CRISPR gene-editing machinery with instructions for the new gene that researchers want to introduce. The gene editor cuts the organism’s DNA and repairs it with the coupled instructions, inserting an entirely new gene into the animal or plant’s genome. 

The new version, which Bier and his colleagues call “allelic drives,” instead carry instructions to cut and rewrite an existing gene. Instead of introducing entirely new genes, allelic drives tweak an existing version of a gene, also known as an allele.

undefinedTraditional gene drives (left) introduce instructions for entirely new genes (in yellow). A new version, known as an allelic drive, can make subtler changes in existing versions of genes, or alleles, as shown in dark blue on the right. Credit: Bier Lab, UC San Diego

For example, a pesticide-resistant insect might carry two slightly different copies of a gene that produces the target of a pesticide, but only one allele confers resistance. The allelic drive could be engineered to cut the resistant version of the gene, either eliminating that gene entirely or repairing it using the other copy of the gene, leaving the insect with two identical copies of the pesticide-sensitive version. As engineered insects breed with the native insects, the pesticide-sensitive allele would sweep through the population.

Allelic drives could even be coupled with the standard kind of gene drive. In the case of gene editing to combat malaria, a drive could be engineered to introduce a new malaria-resistant gene to mosquitoes along with an allelic drive that cuts and rewrites naturally occurring genes in the insects to fight malaria using a different route. 

“That would be a double-pronged approach to fighting the parasite,” Bier said. 

In their study, the researchers demonstrated that the technique works in the lab, using fruit flies with versions of the drive engineered to change the flies’ body color from brown to yellow or to change the number of veins they have in their wings. Their next step will be to test if the technique can, over time, sensitize a population of normally resistant fruit flies to an insecticide. And then they’ll try it in organisms where it could have a more real-world application, like the species of mosquito that transmits malaria or a crop plant. 

“This really allows precision gene editing to be married to the gene drive technology,” Bier said.


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