The chatter of lively hens and cockerels fills the air as birds perch, feed and preen in large pens in a high-ceilinged room.
Two technicians wheel a trolley to a vacant pen and carefully transfer three brown hens and a white cockerel from a carrier into the waiting space.
These birds, on the verge of adulthood and soon to breed, will play a key role in a project that aims to safeguard poultry from one of the world’s most devastating livestock diseases – bird flu.
Gene-editing advances
The chickens have been developed at the National Avian Research Facility, part of the University’s Easter Bush campus, in research towards producing poultry that are resistant to flu.
These surrogate birds are sterile and will not produce their own egg or sperm cells. The surrogates, however, carry donor sperm and egg cells from other birds, in which the DNA has been altered to make any resulting chicks resistant – perhaps completely so – to flu.
This pioneering work from the University’s Roslin Institute is grounded in gene editing – the ability to make small, precise changes to DNA to bring about beneficial traits.
Flu prevention
Research led by Professor Mike McGrew has already shown that making two precise alterations on a single gene in chickens enables them to resist – but not completely block – infection from flu, with no apparent impact on their wellbeing.
This development, by editing a gene called ANP32A, marked an encouraging milestone towards completely flu-resistant birds.
Scientists are now building on this in a new stage of research, working to explore combinations of gene edits that will extend the protection offered by the previous edit to afford full resistance to disease.
“When we first challenged gene-edited birds with a low dose of bird flu and saw they were resistant, It was a really great outcome. We thought we had it – that two [small DNA] edits were a cure for bird flu,” explains Professor McGrew. “But the effect of a high dose [of virus] was a disappointment and showed that we weren’t 100 per cent able to prevent flu, and we had to start over.”
Scientific progress
Progress has been made possible by the emergence of affordable, rapid gene-editing technology. In addition, Professor McGrew and colleagues have spent five years optimising the growth conditions for chicken egg and sperm cells in the lab, so that they are ready for development in surrogate birds.
“A few years ago, we couldn’t modify the DNA at all; and now we have a chicken that might be resistant – five years ago we couldn’t have dreamed that we would do that.
“If you have the chance to change an organism’s DNA by editing or breeding, and have a healthier animal as a result, then one potential problem to solve for society jumps out, and that’s bird flu.”
The ability to study gene-editing in live birds such as those at the National Avian Research Facility enables scientists to ascertain the necessary steps towards producing poultry free of flu.
Such an advance could support the livestock industry in managing the threat of a disease that regularly causes extensive culling and incurs significant costs.
Infection spread
Elsewhere in the Roslin Institute, researchers are tackling bird flu from another angle – seeking to understand the virus and how it might evolve, by studying it up close.
Professor of Virology, Paul Digard – a keen observer of bird flu – has been alarmed by the severity and impact of a very harmful strain of H5N1 virus in recent years.
The virus emerged in the winter of 2020, spreading west from Asia in migrating birds. To the surprise of experts, it survived through two consecutive summers in northern Europe, including in the UK, and continued to sweep across continents, killing millions of wild birds and triggering culls of millions of poultry.
Harmful strain
Bird flu virus had become supercharged, Professor Digard explains, and thanks to the efforts of scientists, we now know in biological terms how that happened.
The virus underwent a spontaneous genetic change that meant it could replicate itself more effectively, faster. At the same time, it developed its ability to limit the immune response triggered by the cells of birds under attack.
“The virus made it across the Atlantic, swept through North America, went down to South America, made its way the length of that continent and is now in Antarctica,” explains Professor Digard.
The good news is that the severe virus, having circled the globe, may have peaked in terms of the damage it can cause. Wild birds that survived the infection are now immune, so it has effectively run out of birds to infect.
“We’ve had it for 27 years somewhere in the world, and since the mid-2000s, it’s been a problem somewhere in Europe, but I’m hopeful the serious impacts we’ve seen won’t be repeated.”
Cattle disease
The virus has, however, recently found a new target, infecting cattle in North America.
“It’s swapped a load of genes with less harmful strains of bird flu that were present in North America, and that seems to have changed its behaviour again, and earlier this year, we realised it’s jumped into US dairy cattle.”
The disease has been shown to spill over into wild mammals – foxes, badgers, otters – and from cattle into other mammals, including humans.
Professor Digard is cautious in his assessment of what this might mean: “It’s not a red alert, but it’s definitely amber. Cows are not usually infected with this type of flu, and it’s still not clear how or why this virus has managed it.”
Human infections tend not to be serious, affecting people’s eyes, which are a common entry point for the virus. This leads to conjunctivitis rather than reaching the lungs to cause respiratory disease.
Laboratory analysis
Professor Digard and collaborators are investigating how the flu’s genetic code has changed to enable it to infect cows, which evidence suggests took place after it reached North America.
In a lab suite at Roslin dedicated to bird flu, scientists are studying a cloned version of the virus – tempered to make it safer for lab work – using cell studies and mini-organs to represent those found in birds and cows.
“Some of the changes we’ve seen in the virus’ code are things we couldn’t have predicted. In working on the cloned virus that’s causing cow infections, we’ll seek to understand its behaviour.
“A big goal for me is trying to be able to predict the virus’ next steps – filling in gaps and also trying to forecast how viruses will change in the future. “
“Mathematical models and computational approaches, including those being developed at the Roslin Institute, enable a more proactive approach, so we can head things off before they become a problem. For example, by vaccinating poultry and cows.”
Advancing knowledge
Lessons continue to be learned from the latest episode of bird flu.
Researchers know more about the spread of flu and how it moves between wild birds and the poultry sector, from backyard hens to industrial flocks.
“It’s sharpened our focus on biosecurity [preventing disease in farms]– we are now at the stage of being able to warn farmers what to worry about. And we know more about the virus biology than we did,” says Professor Digard.
“In addition, authorities are considering vaccination in livestock where they historically wouldn’t have. There is currently no market to develop vaccines, but circumstances might shift focus on this.”
Technology and a collaborative approach are key tenets in understanding how best to manage the ongoing threat of bird flu, and are informing efforts to predict how it might develop.
Thanks to technological advances and creative research at Roslin and beyond, the threat of bird flu to livestock birds might one day be a cautionary tale, rather than a reality.
Image credits: two chickens & Roslin- Norrie Russell; Mike McGrew – Edinburgh Innovations; chickens inside – Nathan Stirk/Getty Images; sign – Hugh R Hastings/Getty Images
