21 July 2021

Progress in sheep's clothing

Who needs the technology to create genetic copies of animals

Alla Salkova, "Veterinary Medicine and life"

In the 1990s, specialists of the Roslin Institute (Great Britain), led by biologists Jan Wilmut and Keith Campbell, were actively looking for a method that would make it possible to produce genetically modified cattle as efficiently as possible. One of the areas that needed to be sorted out were changes in cells during development. Scientists were interested in whether skin, brain and tissue cells could be used to create new animals.

The experiments, which lasted for almost two years, did not bring success. Transplanted embryos died, miscarriages occurred, newborn lambs did not survive. Hundreds of studies ended in failure. Scientists were losing the trust of the leadership, and with it, funding.

Probably one of the reasons why they did not give up on experiments was that it was a stage of a very long journey: the first steps towards cloning were made back in the XIX century. German histologist Theodor Schwann proved that all tissues of animal and plant organisms consist of cells. And zoologist August Weisman described the difference between germ and somatic cells.

In the Russian Empire and the USSR, silkworms became the object of research. In 1886, zoologist Alexander Tikhomirov found out that from them, reproducing sexually, it is possible to achieve artificial same-sex reproduction. In the 1930s, biologist Boris Astaurov received genetic copies of the silkworm. And in the 1940s, embryologist Georgy Lopashov laid the foundations of the modern cloning method - he removed the nucleus of a frog egg and placed the nucleus of a somatic cell instead.

Dolly was not the first cloned animal – back in the 1960s and 1970s, British embryologist John Gurdon conducted a series of successful experiments on cloning spur frogs using the Lopashov method. The first mammal, a laboratory mouse, was cloned in 1987 in the USSR. And a year before Dolly appeared, the same Wilmut and Campbell cloned two other sheep – Megan and Morag.

So what was the breakthrough? The fact that embryonic cells were used to create all these animals. Dolly was the first animal to emerge from the somatic cells of an adult. The scientists used a culture of epithelial cells of the udder of an adult lactating sheep that died before the experiment. The eggs were taken from another sheep. Of the 277 cells, only 29 developed to the state of the embryo. And only one of them formed a viable lamb, which was born from a surrogate mother on July 5, 1996. The newborn lamb was named after the singer Dolly Parton, known for her love to emphasize her outstanding bust.

From criticism to industry

The world learned about Dolly when she was eight months old: a small article "Viable offspring derived from embryonic and adult mammalian cells" (Viable offspring derived from fetal and adult mammalian cells) was published in the journal Nature. The story got into the media, and the sheep was talked about everywhere. But soon Wilmut and Campbell faced criticism.

Norton Zinder, a laureate of the National Academy of Sciences of the USA, pointed out the number of unsuccessful experiments and considered the appearance of Dolly more an accident than a significant result. In addition, since the sheep whose udder cells were used to create Dolly was dead, it was impossible to compare their genomes and confirm that Dolly was her genetic copy. He also pointed out that if the original sheep was pregnant, embryonic cells could get into the material. And in this case, this experiment would be no different from the earlier ones.

In 1999, the British newspaper Independent called Dolly a fake at all. The analysis showed that her genome contains the genetic material of an egg donor sheep. This is due to the fact that 0.02% of mammalian genes are not in the cell nucleus, but in the mitochondria – so the donor genes became part of Dolly. According to critics, this made Dolly not a full-fledged clone, but rather the daughter of two mothers.

But, despite the claims, Dolly's birth was a breakthrough that allowed the use of adult cells for cloning. Soon clones of mice, goats, cows, pigs appeared, created on the basis of cells of both living and frozen animals that had been frozen for a couple of years. Experiments around the world have improved the technology and reduced the number of attempts required to obtain a viable clone by dozens of times. Scientists have made sure that clones are born healthy and are able to give healthy offspring.

Today, China produces about 500 cloned pigs a year to test new drugs. There are also experiments on cloning genetically modified macaques to study some diseases. Another possible scope of cloning is the revival of extinct species and the preservation of endangered ones. So far, however, scientists have not been very successful in this. The gaur bull, cloned in 2001, died two days after birth. In 2003, a clone of the extinct Pyrenean ibex died shortly after birth due to a lung defect. For the second decade, the idea of cloning a mammoth has been discussed in various countries, including Russia, but for this it is necessary first to obtain or artificially recreate its DNA.

There were, however, successful experiments. In 2003, it was possible to clone an endangered banteng bull, later a steppe cat. In 2020, it became known about the cloning of a black-legged ferret, as a result of which a female was born, named Elizabeth Ann. Scientists hope that this experience will help to combat closely related interbreeding – cells of a female who died in the 1980s were used to create an individual, so Elizabeth Ann differs significantly genetically from modern ferrets.

Commercial cloning of pets is practiced in the USA, China, and South Korea. Some companies have a representative office in Russia. But few people can afford a copy of a pet – they will have to pay more than 100 thousand dollars.

The issue is largely economic

There is no targeted research program in the field of cloning in Russia. But in recent years, two important experiments have become known. Scientists from the Federal Research Center of Animal Husbandry – VIZ named after Academician L. K. Ernst were the first in Russia to clone a cow by changing its genome. This event should be the first step towards the creation of genetically edited animals with the desired properties. And the company "Artembriogen" (a resident of Skolkovo) has developed a new approach to cloning, which is called the technology of genetic lift: the egg of the most genetically valuable cow is fertilized with the sperm of an equally genetically valuable bull, and then the resulting embryo becomes a source of material for embryos-clones of a certain sex with specified genetic characteristics. The genetic material of grown calves is used for further reproduction.

"Animal cloning technologies are not used in agriculture in Russia, so far they are at the level of scientific research and startups," Vadim Khlestkin, director of the All–Russian Research Institute of Genetics and Breeding of Farm Animals, a branch of the Academician L. K. Ernst VIZ, told our publication. – The situation is similar abroad, it's just that startups are richer and there are more of them. The real sector is waiting for the cost of the cloning operation to fall below $1,000 per animal. Upon reaching this threshold, the widespread introduction of new technologies is possible, which is likely to happen abroad – farmers who have not implemented them will simply lose out in the competition. Perhaps Russia should develop its own cloning technologies and introduce them first of all in countries where the problem with food is most acute."

As for food products based on meat of cloned animals, in the USA they are considered harmless, adds Vadim Kamilevich, but the position of other countries may differ. From the point of view of science, most likely, products from cloned animals are harmless – they should not differ from products from clones that were born naturally – identical twins.

"The permission or non–permission of a particular technology to be used is largely an economic issue," the expert of "VISION" notes.

– It is better, of course, to regulate it so that the money earned on technology remains in the budget of Russia." Today, cloning is relevant as a tool for copying animals with outstanding characteristics – for example, especially valuable bulls for obtaining and preserving their seed. However, in practice, this is rarely used – there is no shortage of high-quality individuals in new generations, so there is no sense in cloning them yet.

In addition to the cost and technical complexity of cloning, there are other disadvantages – excessive fascination with it can cause problems with genetic diversity. "Cloning is a technology of reproduction of the existing genetic fund, but not its development," Vadim Khlestkin draws attention. – Theoretically, a situation is possible when, to put it simply, all farms will want clones of one, the most economically profitable animal. At the same time, all care for the preservation of genetic diversity will fall on the shoulders of science, museums and nature parks." Risks can be reduced with the help of a centralized, or planned, economy – for example, to provide for the cloning of different genotypes in different farms.

Cloning has other disadvantages: it does not allow to shorten either the breeding or the reproductive process in time. The risk of accidentally cloning an animal with a genetically determined low resistance to diseases or a genetic defect cannot be discounted. But, despite the disadvantages, cloning technology continues to develop – its capabilities, especially in combination with genome editing, are important for research tasks, agriculture, police service and many other areas.

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