The birth of the first genetically modified and cloned puppies

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With the advent of CRISPR-Cas9 gene editing technology, more and more daring genetic manipulations are emerging. In particular, scientists have begun to apply the technique to dogs. By combining gene editing with somatic nuclear transfer cloning, Korean researchers have for the first time produced beagles whose modified genes are more stable and spread more evenly from the first generation. This method may ultimately limit or even eradicate genetic diseases in purebred dogs, or allow the development of more targeted and precise treatments. But the limitations of the method are still little known and may raise ethical concerns for animal advocates.

Nearly 36,000 years ago, humans began to domesticate wolves (Canis lupus), from which most of today’s dog breeds (with a few exceptions) are descended, including domestic dogs (Canis lupus familiaris). Thus, thousands of years of domestication of the wolf had to gradually change its genome so that it gradually adapted to human needs and preferences. This evolution occurred through the process of natural selection or as a result of human migration – domesticated dog breeds crossed and mixed on different continents.

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

In dogs, the CRISPR-Cas9 method was first used in 2015 by Chinese researchers on the same breed. The two dogs born from the experiment were surprisingly more muscular than average, thanks in part to the deletion of the myostatin expression gene, which normally limits muscle development. Obviously, the goal was to develop a new breed more suitable for running and hunting.

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

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

“Positive traits resulting from gene editing can be passed down from generation to generation,” said Liangxue Lai, a researcher at the Guangzhou Institute of Biomedicine and Healthcare Key Laboratory of Regenerative Biology and one of the authors at the time. on Hercules and Tiangou. “It will be possible to breed a large number of genetically modified dogs that can be sold,” he added.

With regard to somatic cloning by nuclear transfer, it has already been used in dogs in South Korea to produce the black and white Afghan Hound. Named Snappy, the greyhound was born from her father’s ear skin cells fused with the eggs of a surrogate female.

Advantages of the two combined methods

In a new study published in the journal BMC Biotechnology, Korean researchers have succeeded in combining this cloning technique with CRISPR-Cas9 gene editing. With this combination, no selection is required to fully express the desired genes.

The main advantage of the new method is the ability to eliminate pathological genetic mutations in purebred dogs. In the latter, indeed, the lack of genetic diversity often leads to a more frequent occurrence of phenotypically recessive mutations. Thus, the ToolGen technique could modify these genes without risking changing other traits, and keep the dog breed pure.

This technology can also contribute to the protection and conservation of biodiversity by applying it to endangered species. For the survival of their species, these animals are often forced to breed between close relatives because their numbers or their territory are too small. Inbreeding, leading to more frequent occurrence of genetic pathologies, therefore represents an additional threat to the survival of these species. Korean technologies could potentially solve this problem by eliminating pathogenic mutations.

In their experiments, the researchers took skin cells that had been induced to mutate the DJ-1 gene to prevent the expression of the protein it encodes. This gene is especially associated with various diseases such as Parkinson’s disease. Other genes have also been added, including one that expresses green fluorescent protein, to make it easier to track successfully modified cells.

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

However, as a result of this experience, only two puppies were born, who are now 22 months old and do not have any abnormalities. However, because diseases caused by DJ-1 are age-related, dogs can develop pathologies with age.

The researchers also stressed that these animals will only be used for medical research. Moreover, such experiments are still the subject of many ethical disputes.

BMC Biotechnology.

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