Gene drives and the rapid rise of resistance

For nearly 60 years, the potential of gene drive systems (GDS) to suppress diseases like malaria and dengue or control invasive species such as cane toads or carp has been theorised — and with the advent of CRISPR/Cas9 gene-editing technology, it seemed that potential had taken a great leap forward.

However, the latest research by a team from Cornell University has found that current approaches to gene drives may need to be rethought.

Ever since natural forms of gene drive were discovered in mice and fruit flies, it has been theorised that a ‘perfect’ GDS could be engineered to suppress or destroy an entire population. This theory has engendered a great deal of excitement as well as concern about the potential bioethical and biomedical questions raised by the idea that the escape of a GDS into a beneficial species could result in disaster.

With the discovery of CRISPR/Cas9 — a bacterial nuclease system — it seemed that the possibility to create a self-perpetuating gene drive that could be deployed in any location, on any eukaryotic species, was close to reality.

The theory is that new genes can be quickly spread through natural populations using CRISPR/Cas9 to suppress undesirable traits. In practice, mutations that prove resistant to the GDS develop too quickly for the system to be effective.

Cornell University researchers set out to prove the effectiveness of the GDS theory using two different CRISPR gene drive constructs in the model fruit fly Drosophila melanogaster. Published in PLOS Genetics, their results showed that the evolution of resistance imposes a drastic limitation on the effectiveness of current CRISPR gene drive approaches, which rely upon a phenomenon known as super-Mendelian inheritance.

The researchers found that resistant gene variations appeared before fertilisation in the germ line, and within the embryo, far more frequently than had been anticipated. In wild populations with genetically diverse backgrounds, this resistance is even more likely.

Ongoing research into contained populations may prove more effective, but the Cornell team believe that future research should focus on new gene drive approaches in order to get around the challenges posed by resistance, especially in genetically diverse natural populations.

This article derives from the Perspective piece ‘The gene drive bubble: new realities’, published by James J Bull and Harmit S Malik under CC BY 4.0

Image caption: Fruit flies with a CRISPR gene drive carrying a red fluorescent protein as payload. Image courtesy of Jackson Champer under CC BY 4.0