A virus genetically engineered to spread its DNA to other viruses via CRISPR gene editing has done exactly that in tests in mice. The hope is that these viruses could alter others, such as herpes, in a way that prevents them from causing symptoms.
鈥淚t鈥檚 a new technology,鈥� says team member at the Fred Hutch Cancer Center in Seattle, Washington. 鈥淐an we bring it to people? That鈥檚 a long way ahead, we have a lot of work to do, but I think this is an exciting technology.鈥�
This approach is known as a gene drive, when a bit of selfish DNA somehow manages to get passed down to a higher proportion of offspring than normal. This means gene drives can spread through a population even if they are disadvantageous.
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In the past century, scientists have discovered many natural gene drives that work via a wide variety of mechanisms.聽Then, in 2014, at the Massachusetts Institute of Technology and his colleagues outlined how . By 2018, CRISPR gene drives were working in caged mosquitoes, with the aim of stopping the spread of malaria.
In animals that reproduce sexually, CRISPR gene drives work by copying and pasting themselves from one chromosome to another, meaning they end up in all eggs or all sperm 鈥� and thus all offspring 鈥� instead of half, as would usually be the case.
A virus doesn鈥檛 reproduce sexually. Instead, it reproduces by getting the cell it infects to make lots of copies of it, so the assumption was that gene drives couldn鈥檛 work in viruses. But cells are sometimes infected by more than one type of virus at a time, and Walter realised that such co-infections provide an opportunity for gene drives to work.
If a gene drive-carrying virus infects a cell at the same time as a normal virus, the gene drive can copy and paste itself into the DNA of all the new viruses being made. If further co-infections keep happening, eventually all the viruses causing an infection inside an individual will carry the gene drive.
鈥淚 got this idea of, 鈥極h, let鈥檚 try to make a gene drive鈥�,鈥� says Walter. 鈥淎t that point, it was a bit of a crazy idea, but we ended up making it work.鈥�
In 2020, his team reported that . When cytomegaloviruses with and without a gene drive were introduced, the gene drive spread until it was carried by more than 95 per cent of the viruses.
The reaction of most biologists to the paper was that viral gene drives wouldn鈥檛 work during a real infection because they thought co-infections were much rarer in bodies than in cells in a dish.
To prove the sceptics wrong, Walter鈥檚 team infected mice with herpes simplex 1 viruses in which 15 per cent of the viruses carried a gene drive. After four days, the proportion of viruses with the gene drive had risen to between 60 and 90 per cent.
This shows that viral gene drives can work in animals, but there are some major limitations. The approach will work only with DNA viruses, not RNA ones such as flu and covid-19 because, among other things, RNA viruses are typically too small to carry a gene drive.
The approach will also probably be most useful for treating persistent infections 鈥� for instance, in people with weakened immune systems 鈥� or latent infections, where viruses lie dormant in cells and occasionally reactivate, as happens with herpes.
With infections that last only a week or two, giving a gene drive to an individual probably wouldn鈥檛 help much by the time they were diagnosed.
If, however, a gene drive were allowed to spread from individual to individual, this could make all the viruses circulating in a population less dangerous, but Walter neither aims to do this nor thinks it would ever be allowed.
He is now testing ways of using viral gene drives to prevent dormant herpes viruses from reactivating and causing symptoms. However, regulators may be reluctant to approve treatments designed to spread their DNA, even for treating individuals. Existing live vaccines sometimes spread pathogens to non-vaccinated people and the risks would be greater with gene drive-carrying viruses.
鈥淭he issue of unwanted transmission to other individuals would need careful investigation,鈥� says Esvelt, who now focuses on the risks of biotechnology. This would be hardest to prevent with viruses that can cause latent infections, he says. 鈥淎s far as current medical ethics is concerned, that would be a non-starter.鈥�
Yet even if viral gene drives are never used for treating people, they could still teach us a lot, says Walter. 鈥淭he fact that we鈥檙e seeing such a high level of co-infection tells us about the way the virus spreads naturally,鈥� he says. 鈥淲e鈥檙e developing the technology, but also discovering some interesting biology.鈥�
bioRxiv
Article amended on 3 January 2024
The article has been updated to make it clear that the research is still at a proof-of-concept stage.
