GMO hen resistant to bird flu

Whether an animal is susceptible to a certain virus or not is anchored in its genes. But what if we could change this record by making them immune to a particular infectious disease? It's an idea worth testing, say British scientists who have just announced the results of 30 years of research. Will we get fried chicken out of it?

It is known that the egg came first, not the hen, because eggs were already laid by reptiles - including long-extinct dinosaurs, to which the hen is evolutionarily close. Scientists at the University of Edinburgh and Imperial University London have genetically modified hen cells, which then gave rise to embryos in fertilised eggs. These eggs produced hens capable of laying mutant eggs and cockerels with mutant sperm. They were crossed and their offspring did not contract avian influenza. What also matters is that the most dangerous variants of this virus for humans are a 'genetic cocktail' of avian and swine flu.

A healthy broth? Not necessarily

It used to be said: 'If a poor man eats a chicken, it means that one of them is sick'. In the 20th century, the farmer's chicken became synonymous with Sunday broth. Today it is a meat that is not very rich in flavour, therefore heavily seasoned, but eaten daily because it is cheap and available to everyone in our culture. Without going into the question of whether this is good for our health, the welfare of chickens and the planet, let us now focus on the consequences of this mass rearing of poultry for the epidemiology of viral infectious diseases (only such rearing provides people with cheap meat).

Both influenza pandemics (above all the famous 'Spanish flu') and the spread of Asian influenza viruses to humans have always had this 'bird genetic' component. This is because the influenza virus loves to mix between variants more than almost any other. To do this, at least two of them have to find a warm place in an animal or human host at the same time.

These are the so-called orthomyxoviruses (Orthomyxoviridae). The most widespread of these is the influenza A virus (FLUAV), which can infect birds and pigs, while some variants can cause epidemics and pandemics in humans. A virus is described by its two proteins, haemagglutinin (H) and neuraminidase (N). This is why the symbols for pandemic viruses are e.g. H1N1 or H5N1 etc.

The price of poultry meat has been rising dramatically for several years. This is not only due to the increased prices for the energy needed to keep these animals (chickens need heat), but also to the decimation of the flocks on farms due to bird flu. There is no cure, and to prevent the spread of the epidemic (which is now prevalent in Eurasia), it is necessary to cull and cremate entire populations.
Egyptian workers check chickens at a hatchery in Sadat City in 2007 due to the spread of the bird flu virus. As a result, the authorities decided to step up controls at the harbour entrances and set up sampling stations for migratory birds along the borders. Photo: PAP/EPA/Khaled Elfiqi
For a long time it was a mystery why poultry is susceptible to the flu. In other words, what is it about the protein of chickens, ducks or turkeys and what specific mutations in it cause a certain flu virus to 'take possession' of it, penetrate the animal's cells and multiply in them. And then it destroys them and leaves them to infect other poultry.

Without this knowledge, it is impossible to fight the virus effectively before it can spread. Simply put, if we create a hen that does not produce a protein that is attractive to the flu virus, the bird will not get sick, the virus will not multiply in it and the chain of infection will be broken. What if we had hundreds, thousands, millions of such chickens...

British specialists have been working on this topic for 30 years. Also at the famous Roslin Institute at the University of Edinburgh, where Dolly the sheep was cloned. Finally, the 'long-awaited achievement' found its way onto the pages of Nature Communications. And all thanks, as in recent times, to the use of the gene editor CRISPR/Cas-9, for the development of which the Nobel Prize in Chemistry was awarded three years ago.

One mutant after another

As in nature - even in genetically modified nature - countermeasures are naturally taken. Poultry farmers will soon no longer be able to buy flu-proof chicks for their farms. This is because chickens whose genome has been modified with CRISPR/Cas-9 were still infected when they were attacked by the flu virus in higher concentrations. This means that as long as there were virus particles in the amount that is common in infected farms, everything was fine, but when there was much more virus, the birds became sick.

Worse still, there is always a risk that such hen resistance will trigger the selection of virus variants that are nevertheless able to circumvent this barrier and attack the animal despite changes in its protein (called ANP32A). What is this all about? As the scientists explain, in order to make the hen immune, only two amino acids in the protein that makes it up had to be exchanged for another. The virus could then no longer bind to it, meaning that it did not reproduce and the infection was "unsuccessful". These changes were therefore made in the chickens' reproductive cells - the precursors of eggs and sperm - and thus paved the way for breeding chicks with the desired mutations. The hatched mutants were then crossed with each other until it was possible to obtain pure lines in which both variants of the chicken's ANP32A gene were altered and the birds looked ' healthy'.
Łódź, 20 March 2020 - A sign announces the danger of bird flu infection. An outbreak of the disease was discovered on a farm in Leaf Street, among other places. The ducks bred there were culled. Photo: PAP/Grzegorz Michałowski
But here, too, there were unforeseen reactions. The influenza virus, administered in excess (two-week-old chickens were injected with the virus through their nostrils), broke down this resistance - not only because there was a lot of it, but also because the virus itself mutated within the chicken cell. As the virus mutated, its gene (called IAV) created a protein that could not only bind to the bird's bioengineered protein (this ANP32A), but unfortunately also worked when the chicken did not produce this protein at all (i.e. when ANP32A was completely removed from the chicken).

This means that the enzymes of the virus, which are essential for the replication of its own genetic material in thousands and millions of copies, were bound to other similar chicken proteins: ANP32B and ANP32E... To contain the invasion of this flu mutant, it was therefore necessary to completely remove all three proteins from the chicken genome.

But proteins - which have been present in our cells since time immemorial and have been polished like diamonds by evolution - are necessary for us. The same applies to chickens. It is not clear that it is so safe to sit on a perch without all these ANP32 family proteins. What's more, the virus mutants that arise in genetically modified chickens could be even more dangerous for humans. So the British experiment is more proof that the genome of chickens can be altered to make them immune (to some degree) to a widespread epidemic virus than it is a way to get flu-proof chickens on chicken farms.

At the very end, we will have to determine whether such a chicken with altered proteins still tastes like chicken at all. Although, on the whole, farmed poultry tastes exactly the same as it has been (over)flavoured...

Chinese poultry specialists (and there are many of them, as China is the world's largest producer and consumer of this meat) remind us in their commentary on the study that influenza viruses often mutate, if only because they move from host to host. For it is their organisms that put the biggest obstacles in the way of influenza viruses. For example, the ANP32A proteins of chickens and humans differ not only in terms of mutations, but also in terms of length, and considerably so (30 amino acids difference).

The fact is that when an organism is attacked by thousands of times as many virus particles, there will always be a 'breakthrough' and an infection - in every chicken there is, including those created by bioengineering. "Nevertheless, the infections in them developed more slowly and reached lower virus levels than in wild birds. Even if they were infected, genetically modified birds were much less likely to transmit the virus to non-modified chickens," concluded Wang Xiaojun, virologist at the Harbin Veterinary Research Institute of the Chinese Academy of Agricultural Sciences for the portal 'Science'.

Sometimes this is the main goal of epidemiology. To reduce the scale of the problem. Of course, we would dream of a system that is so airtight that the influenza virus cannot replicate in birds at all. If that is even possible.

With this idea, no transgenic animals are created - no genes from a dog or a donkey, for example, are inserted into a chicken. So if such an ultimately flu-resistant lab-grown chicken can live on a chicken farm, the government and international authorities set up for this should have no major objections. Although, of course, the question that was persistently posed to the oberleutnant von Nogaj in the psychiatric hospital in the film "C.K. Deserters" flashes before my eyes: "What is that? Are you sure it's a chicken and not - let us say - a dog? Do you want to say categorically that it is a hen after all? Or is it such a hen which somewhat resembles a donkey?"....

– Magdalena Kawalec-Segond

TVP WEEKLY. Editorial team and jornalists

–Translated by Cezary Korycki

Main photo: Debnica, 2017 Due to the spread of the highly pathogenic virus known as bird flu, there was a total ban on releasing domestic fowl and selling live poultry at markets and fairs throughout the country. It was also forbidden to organise exhibitions with domestic birds and to release pigeons. The local authorities maintained the registration of poultry. Photo: PAP/Tomasz Wojtasik
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