Most infectious disease experts believe that the next big flu pandemic is not a matter of if but when. A global outbreak infecting millions of people is not only overdue but, because of increased human travel, is likely to spread around the world in record time.
But much of pandemic preparedness involves damage limitation – that is, stopping the virus spreading once it has started to pass from human to human.
But what if we could kill a pandemic before it even starts, by stopping it infecting the animals who are responsible for passing the virus onto humans?
The source of all pandemic influenza – including the devastating Spanish flu outbreak of 2018 and the 2009 swine flu epidemic – is wild birds, mainly ducks and geese who carry the virus as they migrate. This virus then jumps into farmed animals, usually chickens or pigs, who then pass it on to people coming into contact with them. At some point the virus mutates so that it can then spread easily between humans.
But now, a team of scientists at Imperial College, London and the Roslin Institute in Edinburgh – home of Dolly the sheep, the world’s first ever cloned mammal – are using gene-editing technology to develop chickens that are resistant to pandemic flu viruses.
Influenza causes disease by replicating inside the cells of its host and stealing protein, says Wendy Barclay, professor of virology at Imperial. Four years ago her team discovered the identity of one of the host proteins that flu viruses are dependent on.
They found that during an infection flu viruses hijack this molecule, called ANP32A, and use it to replicate themselves.
“We conceived that if an animal doesn’t make that protein or if it makes a sufficiently altered version of the protein it won’t be infected at all by influenza viruses and it can’t pass onto us what they don’t have,” she says.
Scientists at the Roslin Institute have used the Crispr Cas-9 gene-editing tool to remove the section of the DNA responsible for producing ANP32A. Crispr technology is a revolutionary tool for editing genomes, allowing researchers to easily alter DNA sequences and modify gene function.
“Using Crispr we can genetically engineer just that one change into the animal and the rest of the animal stays the same, retaining all the benefits that have been bred into it through years of traditional breeding by the farmer,” says Prof Barclay.
Outlining their results in the journal E-Life the scientists found that the flu virus was no longer able to grow inside cells with the genetic change.
All the team has at the moment are cells – the next step will be to produce the gene-edited chickens. They will implant the cells into surrogate eggs with the aim of hatching around 10 to 20 chicks – work which will start some time within the next 12 months.
When the chicks are about three weeks old they, alongside “normal”chicks – those whose genes have not been edited – will be exposed to the flu virus to see how both types of chicks react.
The idea of creating a flu-resistant chicken is not a new one. In 2011 scientists from the Roslin, in collaboration with Laurence Tiley at Cambridge University, announced that they had introduced a new gene into chickens that meant that while they could still contract avian flu and become ill they did not transmit the infection to other chickens. The work was promising but the genetic change did not produce a strong enough effect.
This was a transgenic chick, rather than a gene-edited one, and the process of creating it was more complex. The advent of Crispr Cas-9 means that gene editing is now much quicker and easier – however, the outcome is still far from certain, says Professor Helen Sang from the Roslin.
“We’re keen not to oversell the science before we have the birds. This work is very much a hypothesis but because this is an area of significant public interest we don’t want to be seen to be hiding it,” she says.
The first question to establish is whether the birds are healthy – does the genetic change make them more vulnerable to other pathogens, do they reproduce normally, do the birds develop in a normal way?
“The main risk would be that the flu virus could overcome this genetic block – but when we make the birds we can address that,” says Prof Sang.
She believes one of the biggest hurdles will be a regulatory one – that is, getting the necessary go-ahead from government bodies.
Researchers at the Roslin have used the same Crispr gene editing technique to create a pig that is resistant to a virus that causes severe breathing problems in young animals and fertility problems in females. The virus is a huge problem in China and leads to the culling of many animals.
A United States-based genetics firm, Genus, is now working with breeders in China to develop these gene-edited pigs.
“The regulatory bit is the unknown,” says Prof Sang. “Genus is leading the way and if that goes through it will set the standard and lay out the steps so we can follow them,” she says.
Another hurdle will be persuading the public that gene-edited chickens are safe.
“When I talk to people there are those who don’t approve at all with fiddling with an animal’s genes. But we have been doing this for centuries by breeding them,” she says.
Once all these barriers are overcome it would then be fairly straightforward to introduce the chicks with the genetic change, says Prof Barclay. She says that the structure of the worldwide poultry industry is such that the majority of farmers buy eggs from a handful of suppliers so seeding the gene-edited chickens would not be an insurmountable task.
“[The suppliers] have precious founder chickens from which all the eggs are bred and then shipped out all over the place. So what you need to do is persuade those companies that it is commercially viable to incorporate gene editing into their stock,” she says.
“It looks like an impossible task because there are so many chickens everywhere but actually because of the pyramid structure of the industry it’s not that difficult.”
The work is embryonic and while the technique may one day stop a recurrence of the pandemics that have killed millions over the last 100 years, it doesn’t mean that flu will be a thing of the past.
“This only works on pandemic flu. Chickens don’t get seasonal flu,” says Prof Barclay.
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