Category: Science

Translation. Region: Russian Federal

Source: Novosibirsk State University – Novosibirsk State University –

As part of the 63rd International Scientific Student Conference, which was held at NSU in the second half of April, candidate of biological sciences, head of the laboratory of developmental genetics of the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences (ICG SB RAS), associate professor of the Department of Cytology and Genetics Faculty of Natural Sciences, Novosibirsk State University Nariman Battulin gave a popular science lecture, “Farm of the Future: How Genetic Technologies Change Animals.” The scientist told conference participants in an accessible form about how geneticists can influence the genome of farm animals.

How to read a genome?

A geneticist reads genetic texts (genomes) the same way we all read books or posts on the Internet. There are only 4 letters in DNA – A, T, G, C, but one line of the human genome contains 3 billion letters. These texts describe all the characteristics and features of living organisms, right down to eye color and perception of cold. Geneticists study these texts with great interest and try to decipher them.

— The control section of DNA switches on and off certain genes in the right organ at the right time and at the right stage of development. If we learn to understand the “genetic texts”, we will be able to control the properties of organisms. Replacing just one letter can lead to dramatic changes. For example, “turning” brown eyes into blue. Naturally, this excites the imagination of scientists, because it opens up huge opportunities for them. Knowing the DNA “texts”, it is possible to solve many problems in various fields. The simplest is forensics: if the perpetrator left his DNA at the crime scene, it can be read and certain properties of his body and even some details of his appearance can be restored. A more difficult task is genetic modification. If we learn to modify DNA, we will be able to artificially set the properties of the organism we need. To do this, we need to solve a big interesting problem — learn to find those sections of DNA that are responsible for the formation of a certain feature, — explained Nariman Battulin.

The scientist said that geneticists learn which letters in the DNA “text” are responsible for certain properties of the body using genome-wide association studies (GWAS), which helps scientists identify genes associated with a certain disease (or other trait). This method studies the entire DNA set (genome) of a large group of people, identifying small variations called single nucleotide polymorphisms or SNPs. It is based on a statistical procedure that determines the significance of the difference of a particular SNP between groups of people with and without a trait. In this way, it is possible to identify areas of the genome responsible for eye color or hair structure, cognitive abilities and mental characteristics. Up to the genes responsible for a person’s sense of musical rhythm or sense of humor, as well as the grades they receive in class or the level of income they will be able to achieve. Thanks to such studies, geneticists, if a person detects any pathology or body trait, can determine in which area of the genome the gene “breakdown” occurred.

More muscles!

In animal husbandry, similar studies are aimed at identifying genes responsible for economically valuable traits in animals, such as muscle mass in cattle, pigs and sheep, or egg production in birds. Geneticists have learned to identify regions of the genome that enable cows to produce record milk yields, which has revolutionized agriculture, because since this approach was first used to identify the best milk or meat producing animals, there has been a significant increase in agricultural productivity. This approach is no more than 10 years old, but the results achieved during this time allow us to look to the future with optimism and confidently predict further growth in productivity in the livestock industry.

There is another approach: geneticists look for genome sections responsible for any pathological features of an organism by studying the genomes of animals with deformities. “Breakdowns” of genes can lead to the strangest changes in the phenotype of organisms. These changes are an excellent source of information for searching for DNA sections responsible for their development.

Nariman Battulin mentioned the Belgian Blue cow breed as an example. Its characteristic feature is hypertrophied, sculpted muscles. It seems that this is how a product of genetic engineering should look, but no. The reason for this was not the experiments of geneticists, but a random mutation in one gene, which increased muscle growth. It happened quite a long time ago, but was fixed by breeders by selecting individuals with increased muscle mass as an economically valuable trait. Then it turned out that the initial mutation occurred as a result of a “breakdown” of just one gene – myostatin, which prevents the formation of an excessive number of muscle cells. If this gene is knocked out, nothing prevents muscle growth and their volume increases twice as much as normal. And scientists quickly learned to use this.

There is another effective way to interfere with the genome of living organisms. Since they are all distant relatives and have a common ancestor, they also have common genes. If a “broken” myostatin gene is found in cows, this may indicate that a similar gene is present in other animals, and most likely, in their organisms it is responsible for the same trait or property.

There is only one example in the scientific literature of a “breakdown” in a gene that prevents excessive muscle growth in humans—the same one that affects Belgian Blue cows. This is a boy born with a knockout of the myostatin gene. The baby had twice as much muscle tissue as his peers.

— It would seem that here it is, an alternative to grueling workouts in gyms: it is enough to block myostatin, and relief muscles are provided from birth and without any effort. But this medal has a reverse side. All muscles increase twofold, and even those whose increase directly affects the quality of life and health. For example, the tongue, which is also a muscle.

The complexity of such modifications is that each gene affects many traits at once. On the one hand, myostatin knockout increases muscle growth, on the other hand, it creates problems with nutrition due to the tongue being twice as large, and on the third hand, such massive animals with such a large muscle volume cannot be born naturally. For example, the same breed of cows, the Belgian Blue. Almost always, calves of this breed are born by cesarean section. Therefore, before creating such animals using genetic technologies, one should think: will it be economically justified and is it worth settling them on the farm of the future? Yes, they will give much more meat, but how many veterinarians will be needed if the production of meat from such cows is put on stream? After all, the birth of each calf will be accompanied by a surgical operation, – said Nariman Battulin.

As a result, it turns out that the economic effect of one mutation is not really that impressive due to the additional costs of changing the technology of keeping animals with a knocked-out gene. Genetic engineers should always think through such situations. “Improving” one trait can lead to problems with another. And finding a balance so that the desired genetic variants are productive and economically effective is very difficult. In addition, as practice shows, there are very few of them.

“Genetic scissors”

— From the point of view of fundamental biology, if we want to learn how genes work, we need to study this mechanism in animals in which the mutation occurred by chance. But to better understand this mechanism, we need to reproduce it ourselves, transferring this genetic variant to another organism, and see what happens. Geneticists have several tools for this task. The most popular is the CRISPR/Cas9 genome editing tool. It is based on an element of the bacterial defense system that biologists have adapted to make changes to the DNA of plants, animals and humans. It consists of using short RNA that directs CRISPR/Cas9 to the desired site in the genome. After attaching to the target DNA, CRISPR/Cas9 cuts two DNA strands, allowing scientists to either deactivate the gene or insert a new DNA segment in place of the cut. Just one break is enough to “break” the gene and make changes to the DNA. In essence, this genomic editing tool is a biological molecule that can find the right place in the genome to “hit”. This is very important because the human genome, like the genome of a cow and other mammals, consists of 3 billion nucleotides, and finding the right one is not so easy. Genomic editing tools allow us to do this, – explained Nariman Battulin.

With these tools, the most popular genetic variants can be transferred from one animal species to another. For example, the genome of the same Belgian Blue cows contains a knockout of the myostatin gene, while cows of other breeds do not. It is possible to introduce this genetic change by crossing, but it will take too much time. But with the help of genomic editing tools, it is quite possible to introduce the desired genetic variant directly into the DNA of meat breeds. And such calves have already been obtained.

One of the scientific articles on this topic, “Efficient introduction of mutations into the piglet genome using CRISPR/Cas9,” which was published in the scientific journal Scientific Reports, says that the authors obtained 8 piglets with a knockout of the myostatin gene. And indeed, their muscles were twice as big as those of normal piglets. However, all the modified animals died within a week. But why did genome editing, which is successfully carried out on cows, fail on pigs?

— The thing is that each gene affects not just one function, but several at once. For example, the genomes of Belgian Blue cows contain other genetic variants that compensate for the negative impact of myostatin knockout on the body, while pigs do not have such variants. Therefore, it is important for geneticists to remember that the results of transferring one genetic variant to another genetic background can be unpredictable and undesirable, which is what happened in the case of piglets, in whose genome the myostatin gene was knocked out. But sometimes the results are positive. Lambs successfully tolerated the knockout of the myostatin gene — their muscle mass increased, but, unlike piglets, they were viable. This gene was successfully blocked in fish. In Japan, sea bream was subjected to this manipulation, after which the muscle mass of this species increased by 17%. Experiments on “building up” muscles in these fish continue, attempts are being made to bring genetically improved sea bream to market. But genetically modified salmon has already entered the American market. True, it took the enterprise implementing such a bold project 30 years of work and 100 million dollars in investments. If a regular salmon at the age of 18 months reaches 33 cm in length and weighs 1.3 kg, then its transgenic relative is twice as long and reaches a weight of 3 kg, – said Nariman Battulin.

By the way, the farm of the future will have a place for aquaculture, which is currently becoming an important element of agriculture. Most of the fish that comes to our table are not caught in the wild, but grown in fish farms.

Beneficial mutations

With the help of genetic engineering, scientists can make various useful changes to the genome of animals. For example, depriving cattle of horns, which will avoid many problems, namely, injury to other animals or farm workers.

— There are genetic variants of natural mutations obtained in hornless cows. By identifying the genes responsible for such a beneficial mutation, it is possible to artificially edit the genome of cows of other breeds, and calves will be born that fully correspond to their breed with only one exception — they will not grow horns. At the same time, other features and advantages of the breed remain unchanged. Such calves have already been obtained. Normally, animals of their breed are characterized by long horns, but genetically modified cows of this breed do not have them, — Nariman Battulin specified.

By means of genome editing, it is possible to “adapt” cows to climate change. For example, to global warming. There are genetic variants that allow increasing their temperature adaptation, i.e. resistance to heat stress. For example, if you introduce a corresponding mutation into the genome of Angus cows, “breaking” just one gene, the skin of the genetically modified animal becomes slightly thinner, and the wool becomes thinner, which reduces body temperature by 0.3-0.5 degrees under heat stress. Therefore, despite the fact that the absolute figures are small, from the point of view of the biological system, this is a very significant change.

Cold-resistant animals can be created in a similar way. In this task, geneticists are looking for inspiration in the Yakut breeds of cattle, which can withstand even the harshest frosts. They can winter in open areas, so there is no need to build warm barns. And the reason for such resistance to the cold lies, of course, in their genome. Scientists have identified the very genetic variant that affects the cold resistance of Yakut breeds of cattle. This same genetic variant is found in deep-diving animals, as well as in mammals that can hibernate or significantly change their own body temperature.

— Before actually reproducing these genetic variants in other breeds, it is very important to try to understand the mechanism by which these processes are realized. Therefore, at the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, we created modified mice in which we reproduced the genetic variant of Yakut cows. Now we are trying to understand how these mice feel in low temperatures. We are observing changes in the heart rate of mouse embryos depending on the decrease in the ambient temperature. And there is hope that very soon we will understand how this mechanism works and will be able to create cold-resistant mice. But it is desirable that they do not exist on the farm of the future, — the scientist said.

According to Nariman Battulin, the most impressive thing that could be on a farm of the future is pigs that will become organ donors for humans. Unfortunately, humanity does not have the ability to provide donor organs to everyone in need. Genetically modified animals, whose organs can be transplanted to humans, could become an alternative to regular donors. By many parameters, the only species that can be used for these purposes is the pig. In recent years, significant progress has been made in this area. There are known cases of successful xenotransplantation of a kidney from a transgenic pig to a human in the world. However, after this, the few patients lived very short lives. The record holder was a man who underwent surgery in the United States in January of this year. He has been living with such a kidney for four months now.

— The most complex genetic changes that were made on animals were made on pigs for the purpose of subsequent xenotransplantation. In this case, it is necessary to introduce dozens of modifications into the genome, to “break” the genes that produce proteins that our immune system perceives as foreign. In addition, it is necessary to combine the immune systems and blood coagulation systems of humans and pigs. And many such modifications need to be made — the more, the more successful the xenotransplantation procedure will be. Geneticists from all over the world, including scientists from the Novosibirsk Akademgorodok, are working on solving this problem, — the lecturer noted.

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