Cornell researchers find safer approach to gene drives

By Mark Lynas

March 12, 2020

Researchers at Cornell University have developed what they hope will be a safer approach to gene drives, according to a paper published last week in the journal Nature Communications.

Gene drives can potentially change the genetics of entire species by using the gene editing technology CRISPR-Cas9 to override conventional Mendelian genetics and force a targeted gene to be inherited by all offspring within just a few generations.

Many people hope that gene drives will contribute to beneficial outcomes, such as the eradication of malaria, the reduction of agricultural pests, or the elimination of invasive species from islands in order to prevent the extinction of native animals.

However, the inherent power of gene drives means that once released, the spreading genes could be hard to control. Even if released on islands or other isolated locations, just a few escaped individuals could eventually spread the gene to the whole global population of a species.

The high risk of unintended consequences makes it difficult to carry out field trials of potential gene drives. The Cornell approach mitigates this risk by ensuring that a substantial number of individuals above a certain threshold would have to escape a trial zone in order for the new genes to spread more widely.

In classic gene drives, scientists genetically engineer an individual of a species to pass on the drive genetic sequence to its offspring. Where an organism inherits the drive from one parent, the CRISPR machinery cuts and pastes the drive sequence into the wild-type allele inherited from the other parent.

This means that the offspring has the drive in both its genomes and will in turn pass it on to all of its offspring. The drive will then continue to spread, eventually eliminating wild-type alleles (genetic variants) from the entire population.

This basic approach has been shown to work within confined laboratory populations of yeast, fruit flies, mosquitos and mice. However, the potential for uncontrolled spread of drive genes means that even initial testing outside the lab may be too risky.

The new approach developed by Cornell scientists is termed a “toxin-antidote recessive embryo” (TARE) system. In this system, a drive allele is engineered to serve as the “toxin” by targeting a gene which is essential for an organism to function.

The targeted gene is also “haplosufficient,” which means that an organism can survive with only one functioning copy of the gene rather than two. The drive gene cuts wild-type alleles, disabling them — and where an offspring inherits two copies of this broken gene it will fail to survive.

But the engineered gene also carries a “rescue” component, a sequence that enables the gene to still function, though with a slightly different DNA sequence, so it will not be recognized and targeted again. Individuals inheriting one copy of this gene will survive and pass it on.

This means the drive will continue to spread, but it also gives the drive less vigor. In other words, the gene drive should be able to spread more widely only if the initial input of engineered drive-carrying individuals passes a certain threshold.

For example, if just one or two engineered mosquitos escaped a field trial site on an island, they would not threaten the entire global population of the species because many more engineered individuals would have to be released for the gene drive to work.

This “threshold-dependent invasion dynamics” is proposed as a major benefit of the new TARE gene drive system, particularly if the new engineered gene imposes a fitness cost on the organism over and above the loss of some offspring which inherit two broken copies of the target gene.

The scientists write: “Such threshold-dependent dynamics could be desirable for enabling drives to be confined to certain regions, since it would prevent establishment in other regions through a small number of migrating individuals.”

They also note that this is in “stark contrast to homing-type [classic] drives, which are self-sustaining at any introduction frequency in deterministic models.”

The researchers also point out that the dynamics of the new TARE system make it less likely that a species will be able to evolve resistance to the introduced drive genes. This is because DNA changes in the target gene that would enable it to avoid being recognized by the drive system would also make the offspring unable to survive because of the gene’s essential function.

The new paper, entitled “A toxin-antidote CRISPR gene drive system for regional population modification,” was published in Nature Communications on Feb. 27, 2020. The lead author is Jackson Champer, a postdoctoral researcher at Cornell University’s Department of Computational Biology. The paper is open access.

Image: Jill George, NIH