New gene drive ‘off-switch’ could assuage fears of critics

By Mark Lynas

July 6, 2018

Researchers in the UK have developed the first ‘switchable’ gene drive system, potentially addressing fears that the use of gene drives to control malaria or eliminate invasive species might run out of control and have devastating unintended consequences.

Gene drives work by overriding the usual Mendelian laws of genetic inheritance, where offspring have a 50 percent chance of inheriting any particular gene variant from each parent. Gene drives work by ensuring that virtually all offspring inherit the intended gene, spreading it rapidly through the entire target population.

Until now, the fear has been that while gene drives undoubtedly offer a very powerful way to genetically engineer large populations of any target organism, their very irreversibility might preclude their use or even testing outside the safe confines of the laboratory.

The new study, conducted by scientists based at the University of Bath and Cardiff University and published in the Nature journal Scientific Reports, demonstrates the effectiveness of a gene drive on-off switch delivered by the presence of a cheap and enviromentally-friendly amino acid.

Gene drives typically use the CRISPR-Cas9 genome editing system, where CRISPR targets a specific genetic sequence of interest and the Cas9 protein delivers a double-strand break in the DNA. This either causes a mutation that allows a gene to be knocked out or a DNA repair which assimilates an introduced gene.

The authors of the new study demonstrate that the operation of a variant of Cas9 can be controlled by using the amino acid BOC (the lysine derivative H-Lys(Boc)-OH) in such a way that the expression of the Cas9 protein depends on the presence of BOC.

In other words, the gene drive will only work if BOC is ingested by the target organism so that it is present in the cells. This would theoretically allow scientists to regulate a gene drive in the wild merely by adding or withdrawing the amino acid BOC from the environment.

The paper is only an early proof of concept, using transgenic mouse embyros in the presence of BOC under laboratory conditions. How the idea might work in the wider environment on different gene drive target organisms remains to be seen.

Perhaps the most promising gene drive option – one supported by the Bill & Melinda Gates Foundation (which also funds the Alliance for Science) – is the possibility of eliminating malaria transmission by targeting the mosquito species that carry the malaria parasite.

Efforts to reduce malaria in Africa and other tropical developing countries have stalled in recent years as mosquitos have developed resistance to insecticides and the malaria parasite has itself evolved resistance to drugs.

In 2016, according to the World Health Organization, 445,000 people died from malaria, the majority of them children. That equals one child death somewhere in the world every two minutes, health campaigners point out.

In 2015 scientists demonstrated the potential to use gene drive technology to stop malaria by eliminating the ability of the malaria-carrying mosquito Anopheles gambiae to reproduce via a female sterility gene.

The Target Malaria organization, a not-for-profit research consortium that aims to develop and share technology for malaria control, has proposed the use of gene drives to reduce the mosquito population and is currently working in the African countries Burkina Faso, Mali and Uganda. It has said it is hoping to test gene drives in the field as early as 2023.

One of the key stumbling blocks is the ability to stop or reverse a gene drive should something go wrong – such as, for example, the gene ‘jumping’ into a non-target species or mutating in an unexpected way.

Whether the new paper demonstrating an on-off switch for gene drives might deliver such a mechanism for use in the field remains to be seen. The researchers propose its use initially in livestock, where a gene drive might be used to spread a disease-resistance trait. In this case, BOC could be delivered in feed to precisely control the spread of the new genes.

Gene drives have also been proposed as a way of eliminating invasive species from islands in order to save native species threatened with extinction. However, campaigners against genetic engineering have warned of the “dangers of irretrievably releasing genocidal genes into the natural world” and called for a moratorium on gene drive development.

But there are risks on both sides of the equation. For malaria, as a writer for Vox pointed out, “starting from the moment we have deployable gene drive technologies that could wipe out the disease, every day we wait kills between 1,200 and 2,000 people”.

Whether the new switch mechanism elaborated in the Scientific Reports paper assuages some of the fears of gene drive opponents remains to be seen. More research will be needed to demonstrate how deployable it might be at the scale needed to control a gene drive targeting a wide geographical area.