Birth of the first genetically modified and cloned puppies

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Since the emergence of the CRISPR-Cas9 gene editing technique, ever more daring genetic manipulations are emerging. In particular, scientists have begun to apply the technique to dogs. By combining gene editing with somatic cloning by nuclear transfer, Korean researchers have for the first time given birth to beagles whose modified genes are more stable and spread more evenly, from the first generation. The technique could eventually limit or even eradicate genetic diseases in pure dog breeds, or allow the development of more targeted and precise treatments. But the limits of the method are still little known and could raise ethical issues among animal rights defenders.

Nearly 36,000 years ago, man began to domesticate wolves (Canis lupus), from which would descend most of today’s canine breeds (with a few exceptions), including companion dogs (Canis lupus familiaris). The thousands of years of domestication of the wolf would thus have gradually modified its genome, to adapt gradually to the needs and preferences of man. This evolution would have taken place through the process of natural selection, or through human migrations – the domesticated canine breeds would have crossed and mixed across the continents.

Today, man seems to want to influence this genetic evolution more radically thanks to biotechnology. Just recently, researchers from the Korean company ToolGen combined CRISPR-Cas9 technology and cloning for the first time, and gave birth to two apparently healthy baby beagles.

On dogs, the CRISPR-Cas9 technique was used for the first time in 2015 by Chinese researchers, on the same breed. The two dogs born from the experiment were strangely more muscular than average, in particular thanks to the elimination of the myostatin expression gene, which normally limits muscle development. The goal was apparently to develop a new breed more suitable for running and hunting.

This precise, inexpensive technology has inspired many other companies to experiment with new breeds or “revive” pets of wealthy customers. The advantage of this technology would be the elimination of genes responsible for diseases, or even the improvement of cognitive and physical faculties.

However, the basic technique is limited, as the animals born are “chimeras”. With this technique, gene editing takes place directly at the level of the fertilized egg, which is then implanted into a surrogate female. But since the modification is not represented in all cells, breeding is necessary to reproduce the genes at a higher frequency in future generations.

Favorable traits that result from gene editing can pass from generation to generation “, explained at the time Liangxue Lai, researcher at the key laboratory of regenerative biology of the Institutes of biomedicine and health of Guangzhou, and one of the authors of the experiment on Hercules and Tiangou. ” It will be possible to breed a large number of genetically modified dogs, which can be marketed “, he added.

As for somatic cloning by nuclear transfer, it has already been used in dogs, in South Korea, to produce a black and white Afghan hound. Named Snuppy, the greyhound was born from the skin cells of an ear of the father, fused with the eggs of a surrogate female.

The advantages of two combined techniques

In the new study, published in the journal BMC Biotechnology, Korean researchers have successfully combined this cloning technique with CRISPR-Cas9 gene editing. Thanks to this combination, no breeding is necessary for the desired genes to be fully expressed.

The main advantage of this new method is the possibility of eliminating pathological genetic mutations in purebred dogs. In the latter, in fact, the lack of genetic diversity often leads to the more frequent appearance of phenotypically recessive mutations. ToolGen’s technique could thus modify these genes without risking altering other traits, and preserve the purity of the canine breed.

The technology could also contribute to the safeguarding and conservation of biodiversity, by applying it to species threatened with extinction. For the survival of their species, these animals are often forced to reproduce between close relatives, their number or their territory being too small. Inbreeding, leading to a more frequent appearance of genetic pathologies, therefore constitutes an additional threat to the survival of these species. Korean technology could potentially alleviate this problem, by eliminating pathogenic mutations.

In their experiments, the researchers took skin cells where a mutation of the DJ-1 gene had been induced to prevent the expression of the protein that it codes. This gene is notably associated with various diseases, such as Parkinson’s. Other genes have also been added, including one expressing a green fluorescent protein to facilitate tracking of successfully modified cells.

For nuclear transfer, the cells were placed close to eggs from which the DNA had been previously removed. The cells and the eggs were then fused together thanks to electrical impulses introduced into their environment. The 68 embryos obtained were implanted in six surrogate females.

The experience, however, only gave birth to two puppies, who are now 22 months old and show no abnormalities. However, since DJ-1-induced diseases are age-related, dogs could possibly develop pathologies with age.

The researchers also stressed that these animals will only be used for medical research. Moreover, this kind of experiment is still subject to many ethical debates.

Source: BMC Biotechnology

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