Both risks and limitations are inherent in the GM approach. Report: Claire Robinson

Scientists at the University of Edinburgh’s Roslin Institute — the animal research centre where Dolly the sheep was created — have used CRISPR gene editing to develop chickens that resist infection by bird flu, a disease that has decimated some wild bird populations and commercial poultry flocks across the world. But there are serious risks and limitations in the research, which were even indicated by the scientists involved but were largely ignored or downplayed by mainstream media outlets.

A press statement by the Roslin called the gene-edited chickens a “significant step in bird flu fight” and said, “Alterations to key gene associated with infection offer partial protection and suggest [a] path to flu-resistant poultry”. The findings are published in Nature Communications.

The Roslin reported that the scientists used gene-editing techniques to identify and change parts of chicken DNA that could limit the spread of avian flu in the birds. The bird flu virus needs a protein present in chicken cells, ANP32A, to replicate. Prof Wendy Barclay of Imperial College London, a co-author of the study, said, “It occurred to us if you could disrupt that interaction and prevent the protein from being used, the virus would not be able to replicate.”

The team of scientists, led by Mike McGrew, a University of Edinburgh researcher, used the CRISPR gene editing technique to modify the gene that produces the protein in the chickens’ germ cells, which would enable the birds to pass down the change to their offspring. As a result, the Roslin said, “Researchers were able to restrict – but not completely block – the virus from infecting chickens by altering a small section of their DNA. The birds showed no signs that the change in their DNA had any impact on their health or wellbeing.”

When the gene-edited chickens were inoculated with 1,000 infectious units of the virus – equivalent to real-world exposure – only one in 10 birds were infected and shed a very low amount of virus over a few days. All the control birds were infected.

When exposed to an extremely high dose of 1 million infectious units, five of the 10 birds became infected, though with a viral load lower than seen in the control chickens.

The Roslin said, “The findings are an encouraging step forward, but experts highlight that further gene edits would be needed to produce a chicken population which cannot be infected by bird flu – one of the world's most costly animal diseases.”

No “easy button” for flu

The research predictably generated a slew of pro-GMO hype. The Guardian patriotically headlined its article, “World’s first flu-resistant chickens could pave way for gene-edited UK poultry”.

But the New York Times (NYT) was more cautious, emphasising from the start the scientists’ own warnings that the study also highlights “the limitations and potential risks of the approach”.

The NYT cited the researchers’ finding that some breakthrough infections still occurred, especially when gene-edited chickens were exposed to very high doses of the virus. And when the scientists edited just one chicken gene, the virus quickly adapted. The findings suggest that creating flu-resistant chickens will require editing multiple genes and that scientists will need to proceed carefully to avoid driving further evolution of the virus, the study’s authors said.

The NYT quoted Prof Barclay as saying that the research is “proof of concept that we can move toward making chickens resistant to the virus, but we’re not there yet".

The NYT also quoted Dr Carol Cardona, an expert on bird flu and avian health at the University of Minnesota, as cautioning that the results show how difficult it will be to engineer a chicken that can stay a step ahead of the flu, a virus known for its ability to evolve swiftly. “There’s no such thing as an easy button for influenza,” Dr Cardona said. “It replicates quickly, and it adapts quickly.”

Step towards making bird flu more infectious to humans?

In additional experiments, the researchers studied samples of the virus from the gene-edited birds that had been infected with bird flu. They found that these samples had several mutations, which appeared to allow the virus to use the edited ANP32A protein to replicate.

Some of these mutations also helped the virus replicate better in human cells, although the researchers wrote that these mutations alone “are not sufficient to adapt an avian influenza virus to humans”.

While the researchers appeared reassured by that, in GMWatch’s view, they should not be. Triggering these mutations in the virus and facilitating its enhanced replication are important steps towards making bird flu more infectious to humans. There have already been cases, albeit rare, of humans catching bird flu and dying from it. Gene-edited chickens, if they were to be commercialised, could make it easier for bird flu to jump to human hosts and even spark another pandemic.

Commenting on the new research, molecular geneticist Prof Michael Antoniou, who uses older-style GM and gene editing in a clinical research context, warned: “The more you push viruses like flu to adapt, the greater the risk that variants will arise that can cross species, including ones that can now infect humans. This is not unprecedented.”

Multiple genes have to be engineered

The researchers on the gene-edited chicken project also found that the mutated flu virus was also able to replicate even in the complete absence of the ANP32A protein by using two other proteins in the same family. When they created chicken cells lacking all three of these proteins, the virus was not able to replicate. Those chicken cells were also resistant to the highly lethal version of bird flu that has been spreading around the world in recent years.

For this reason, the NYT reports, the researchers are now working to create chickens with edits in all three of the genes for the protein family.

For Prof Antoniou, this is where this venture breaks down. He said, “This research is a very tenuous ‘proof of concept’. The researchers realise that they have to ‘knockout’ multiple genes to get any reasonable outcome. But the more genes you knockout, the less viable the birds become because you disrupt basic biological functions that the animals need just to survive. As a result, in my view, the researchers will run up against a brick wall.”

Prof Antoniou isn’t alone in warning about this issue. The NYT quotes Dr Richard Webby, a bird flu expert at St Jude Children’s Research Hospital who was not involved in the research, as questioning whether chickens with edits in all three genes would still develop normally and grow as fast as poultry producers needed.

In GMWatch’s view, the high adaptability of flu viruses, the risks of this research driving the selection of more human-infectious viruses, the potential to create chickens with health problems or abnormalities, and the overall complexity of life should spell the end of this research, the outcomes of which are all too predictable. But these realities aren’t going to stop these types of studies as long as the money train is still running.

Alternatives to GM

There are several alternative approaches to the bird flu problem that have been ignored or downplayed in the media circus around the gene-edited chicken research.

Vaccines are sometimes mentioned. But attempts to develop effective vaccines for bird flu have proven elusive, because the proteins on the virus’s surface that are recognised by the immune system mutate rapidly. One vaccine has been approved for use in chickens in the EU, but it’s not widely available.

However, it’s clear that genetic engineering isn’t needed to combat bird flu. Earlier research carried out at the Pirbright Institute and the University of Lincoln in the UK found that some poultry lines are naturally genetically resistant to bird flu, without any genetic engineering being involved.

Why this line of research isn’t being aggressively followed up is anyone’s guess. Our guess would be that non-GM naturally flu-resistant poultry lines are not patentable. They are therefore of little interest to institutes that have jumped on the GMO bandwagon, except as a source of genes to “mine” for genetic engineering ventures.

Natural immunity

As well as the things that we could do but are not doing, there are things we are doing but should not.

The process of developing natural immunity in our commercial poultry is also undermined by government official policies of killing entire flocks of birds where even one case of flu has been detected. This means killing the birds that will overcome the disease or not catch it in the first place, when it is those very birds that should be preserved to breed a national flock that is naturally resistant to the disease.

Mass culls make about as much sense as a human flu control measure consisting of killing an entire community of people when one of them catches flu. It’s a recipe for fostering a population with no immunity at all. In livestock farming, such an approach, if aggressively pursued for several generations, could even lead to the mass collapse of certain sectors of the food animal industry due to lack of resistance to disease.

One potential example is the policy of removing from the herd and killing cattle that react positively to the TB antibody test, even when they are apparently super-healthy. More than one cattle farmer has told me that these cattle invariably proved clear of disease in the compulsory followup post-mortem, suggesting that they had been exposed to TB, developed antibodies (hence the positive test), then recovered. The farmers – under their breath and off-the-record – spoke words to the effect that “Some of us know we are killing the wrong animals. These are often the healthiest animals in the herd.”

Intensive farming is the culprit

The most useful and most-needed approach to bird flu would be to end factory farming of poultry. The gene-edited chicken research has justifiably prompted criticism of industrial poultry farming systems, which are incubators for disease. In response to the new study, regenerative farmer Ajay Vir Jakhar tweeted, “This is what is wrong with the food systems; altering a chicken’s DNA to tackle bird flu, which is a result of industrial scale poultry farming.”

Jakhar’s view is backed by a report by Compassion in World Farming (CiWF), which pointed out that while wild birds have taken much of the blame for spreading bird flu among commercial poultry flocks, “the development of highly pathogenic strains of bird flu lies at the door of factory farming”. The report explained, “Whilst not denying that wild birds, backyard and free range farms naturally play a role in the spread” of bird flu, the overwhelming evidence points towards “other often more important routes of spread – namely the global trade in live poultry and poultry products”.

CiWF cites research showing that “The spread of [the bird flu virus] H5N1 from China to Europe, Africa and the Middle East correlates with major road and rail routes rather than bird migratory routes or seasons.”

CiWF concluded, “Keeping massive numbers of poultry on intensive farms worldwide is now coming back to bite us. The solution lies in bringing an end to factory farming and the conditions that can act as a disease pressure cooker, instead rearing animals using humane and sustainable farming methods.”

There is a real risk that in the unlikely event that the GM gene-edited chicken approach were found to work, it would simply encourage and facilitate the type of intensive farming and inhumane conditions that led to the bird flu epidemic in the first place.

CiWF’s report was published in 2007. The Guardian published an excellent article about it, emphasising the report’s demand for “a radical restructuring of the industry to raise healthier birds in better environments”. Yet it seems that the more influential sectors of society have learned little about disease prevention, instead choosing to hype risky and unproven GM approaches that threaten to perpetuate animal suffering and even to spark another human pandemic.

What the new research really tells us

The ”concept” that the new research “proves” can be interpreted in one of two ways. If you strongly believe in the potential of GM to solve the bird flu problem, you could conclude that if a huge amount more work and money is poured into this research line, scientists might succeed in manipulating enough genes to confer sustained resistance to the virus without making the birds themselves non-viable. But our own interpretation is probably more realistic: A single-gene approach to conferring robust viral resistance will never work, a multi-gene approach carries a high risk of creating serious health and welfare issues in the birds, and scientists are still very far from their goal of developing bird flu-resistant flocks through GM.

Image by "L214 - éthique et animaux": A standard chicken farm in France in 2017. From Wiki Commons, licensed under the Creative Commons Attribution 3.0 Unported licence.