Creating CRISPR Chickens

The seasons are changing. Winter is coming. But in the darker days ahead, we still have plenty of scientific breakthroughs to celebrate. 

Bird flu has been appearing in many media headlines as of late. It is highly infectious and considered by the World Health organization to be a potential pandemic threat. I recently wrote an article for our sister publication, ID Transmission, about a new case of human infection from the subtype H3N8, which is already prevalent in birds, horses, and dogs. Our understanding of how H3N8 jumps from animals to humans is limited, but recent discoveries by researchers in the UK and China suggest that H3N8 may be going through mutational changes that increase its spillover.

The World Organization for Animal Health estimates that over 140 million poultry have died worldwide from bird flu or related culling since 2021. And though there are many types of bird flu, a subtype of the influenza A virus – known as H5N1 – has been a particular cause for concern due to cases of bird–mammal transmission and, very occasionally, people. “What was once very clearly a poultry pathogen has now become an animal-health issue much more broadly,” said Andy Ramey, a wildlife geneticist at the US Geological Survey Alaska Science Center in Anchorage, in conversation with Nature. “That has implications for wildlife and domestic poultry as well as us humans that rely upon these resources.”

Not all is doom and gloom
 

To help tackle the problem, UK-based scientists have turned to CRISPR/Cas9 to generate gene edited chickens – CRISPR chickens, if you will.

The study, published in Nature Communications, theorized that weaving immunity into the DNA of chickens could stop the virus from establishing an infection. All subtypes of the bird flu virus rely on “hijacking” a protein called ANP32A – the perfect target to modify. The researchers edited two amino acids in ANP32A to stop the virus in its tracks. And, to some extent, it worked.

“All viruses are obligate parasites,” said Wendy Barclay, a study author and virologist at Imperial College London, during a press briefing. When viruses get inside a host cell, she continued, “They hijack various proteins inside the cell to help themselves replicate.”

The team produced 10 chickens with this altered form of ANP32A before exposing the birds to H9N2 – a milder subtype to H5N1. They then exposed an additional group of 10 non-edited chickens to the virus as a means to compare results. Notably, only one of the 10 edited chickens became infected, whereas every chicken from the non-edited cohort succumbed to the virus.

The scientists proceeded to conduct a follow-up trial, this time exposing the avian subjects to a viral dosage 1000 times more potent than before. And though five of the 10 gene-edited birds became infected, the viral load within their airways was noticeably lower than that observed in the unmodified chickens.

Interestingly, the team also found that the viruses in these birds possessed additional genetic mutations that facilitated replication, making them less reliant on the ANP32A protein. Instead, two other proteins, ANP32B and ANP32E, stepped in and supported the replication process. The researchers finally demonstrated that concurrent gene editing of all three proteins thwarted virus replication in chicken cells entirely.

This research is “proof of concept that we can move toward making chickens resistant to the virus,” Wendy Barclay added.

Genetic resistance in chickens could obviate the need for routine bird vaccinations, reducing the risk of viral mutations that facilitate interspecies transmission.

But we must remain realistic. Achieving complete protection against avian flu through this approach alone may prove challenging. But what about a combination of genetic modification, widespread vaccination, and improved farming practices? Surely, that could pave the path towards highly effective prevention in the future…