Why are we different?
Because the same genes don't work the same way
Yuri Drize, "Search" No. 25-2016
A simple question is "What is your specialty?" Professor Yuri Lebedev caused a difficulty. He is a microbiologist by education, graduated from the Biological Faculty of Moscow State University. He has been working at the Institute of Bioorganic Chemistry for almost 40 years. Academician M.M.Shemyakin and Yu.A.Ovchinnikov of the Russian Academy of Sciences, Head of the Laboratory of Comparative and Functional Genomics. The Candidate of Chemical Sciences and the Doctor of Biological Sciences treats biochemistry with great respect, as well as genetics, molecular genetics, virology... Indeed, it is not so easy to designate your specialty in one word.
– I consider many employees of our laboratory, mainly my former students of the biology faculty of Moscow State University and MIPT, then graduate students, and today – senior researchers, candidates of sciences, encyclopedists, – explains Yuri Borisovich. – Naturally, we do not understand all areas of modern science, but we choose four, and sometimes five or six narrow specialties and combine them quite productively. We are interested in doing everything at once: for example, molecular biology and bioinformatics, to achieve a high professional level in them, and in some ways – and the world, to publish articles in prestigious foreign journals.
Even while studying at the MSU biofactory, I was interested in the issue of gene regulation. Why do the same genes work differently in all people? In the same conditions, someone gets sick, and someone does not? Why does the virus infect one, spare the other – because genetically we are all very similar? In my opinion, most of our differences, even psychological ones, depend on which specific (personal) set of gene variants, called alleles, we received from our parents. And even more depends on how well and harmoniously different groups of alleles can work.
In the early 1990s, as part of the laboratory of Academician Evgeny Davidovich Sverdlov, my group participated in the Human Genome project - we deciphered the primary DNA structure of one of the chromosomes. We found out which genes are turned on and off, where they are, what does gene expression mean in people's lives. Special attention was paid to the "on-off switches" of human genes, for which they compared DNA fragments of humans and our closest relatives – great apes. This new knowledge has a variety of practical applications: for example, finding out the causes of hereditary diseases, the development of individual, or, as they now say, personalized medicine. As well as recreating the picture of biological evolution and defining man as a species from a genetic point of view, given that we did not descend from monkeys, but from common ancestors with them, having undergone all sorts of genetic changes. We are looking for answers to all these questions.
For example, how does a human genetically differ from a chimpanzee? Firstly, it's just interesting, and secondly, comparing both species, we get additional information about the uniqueness of the human genome. The manifestations of this peculiarity are obvious. Residents of Moscow and Hong Kong can be very different in appearance, although both have all the universal human traits that distinguish them from other primate species.
– What is the genetic reason for such obvious differences in people?
– The reason is that even during the period of intrauterine development, the processes of formation of a new organism in humans and great apes differ markedly, since they are controlled by a set of certain genes.
We assumed that even at the early stages of human evolution, about 6 million years ago, our ancestors had mutations in special genes that work only at certain stages of embryo development and regulate the activity of many other genes. One of these regulatory genes (or regulatory genes) - the "speech gene" – determines the formation of the larynx and tongue. A mutation in the speech gene that arose in our distant ancestors leads to the fact that all people have a lowered larynx, elongated vocal cords, a windpipe arises, the muscles of the root of the tongue are modified and the ability to pronounce distinct phonemes appears. And in chimpanzees, this gene works "in the old way", that is, it does not include the necessary complex of other genes in time, and monkeys do not have articulate speech. But this does not prevent individual unique specimens from communicating perfectly with people and even learning. One such chimpanzee has been observed for a long time in the USA. He has mastered the language of symbols and expresses human emotions. They show him "icons" with drawings, explain their meaning – and he understands that if he points to a banana or carrot, he will get them. But he also managed to master much more complex abstract concepts: he knows, for example, what input-output means, the meaning of the words "want" or "desire". And he can't speak – it's not given.
– Have you managed to find out how such regulatory genes appear?
– Yes, and it turned out to be quite simple. In the human genome, in addition to the genes encoding proteins, there are short fragments of DNA, repeated many times and identical in primary structure. For a very long time, researchers did not take these repetitive DNA fragments seriously, because they did not know what these parts of the genome were responsible for. And repeating elements, by the way, occupy almost half of the human genome. Some of them have a unique ability: they reproduce independently of cell division and embed their copies in other places of the genome than the original element occupied. That's why they got the name mobile genetic elements. They are very important because they can change the activity of the genes surrounding the embedding site. Moreover, it should not be changed dramatically, but gently modulating the intensity or time of operation of nearby genes. We began to search for such changes in the human genome and discovered thousands of new copies of mobile genetic elements that are in the DNA of any of the people, but are absent in similar places in the chimpanzee genome.
We were also interested in whether new copies of mobile elements could appear in the DNA of individual human brain cells. Studies have given a positive answer: millions of neurons in the cortex and some other parts of the brain do contain such copies, but the location of the genome, and therefore the genes adjacent to each copy, turned out to be unique for each of the genetically modified neurons. The genetic heterogeneity of brain cells of the same individual that we have discovered may underlie the well-known phenomenon of "functional plasticity of the human brain". So far, this is only a hypothesis, but we are developing it, considering it extremely promising.
– Is it possible to apply this new knowledge in practice?
– I hope so. Changes in the DNA structure of individual brain cells can lead to the formation of new neuronal connections, which will affect human memory, its durability, acceleration of the processes of memorization and learning, as well as improve the reaction and development of cognitive (cognitive) abilities, etc. This will happen because not all neurons in the cerebral cortex are the same. Each has its own little feature. But all together they form a single neural network in which individual "communities" of neurons are engaged in solving their own problems. And functional plasticity is the ability of neurons to move from one community to another or to consist of several at the same time. And the more plastic the brain is, the higher its ability to switch from one thing to another. Now we are looking for examples of the relationship between the genetic diversity of nerve cells and the plasticity of neural networks.
Determining the molecular mechanisms of the functioning of the brain as a whole is an even more complex and voluminous task, this is the next level of cognition. The search for answers to particular questions helps to advance in the development of this problem as a whole, but already today there is an opportunity to apply the acquired biological knowledge in various fields of human activity. The principles of neural networks and functional plasticity are used, for example, in the development of more advanced and complex mathematical programs that simulate the work of the human brain. We are talking about creating fundamentally new systems for transmitting, processing and storing information using mechanisms and processes similar to those that occur in the brain. The development and implementation of artificial neural networks will accelerate the emergence of a new generation of computers and Internet resources capable of self-learning and self-overcoming failures in the collection and processing of mega-volumes of information. In turn, the accelerated development of information technologies brings us closer to the creation of artificial intelligence. And all this will come true if we manage, I repeat, to delve as deeply as possible into the work of the human brain.
– And for the treatment of severe ailments, it will be possible to use the capabilities of neural networks?
– Yes, because such age-related diseases as, for example, multiple sclerosis, Alzheimer's disease, senile dementia are associated with disorders in the regulation of brain functioning, the occurrence of malfunctions in its work. To understand the cause of failures, to learn how to prevent violations in the coordinated work of billions of neurons is the most difficult problem. Therefore, it is so important to accumulate knowledge about the biological system of internal regulation and control of brain activity. It is necessary not only to deeply understand the physiological and genetic features of the human brain, but also to learn how to skillfully correct them – then we can help correct the disorders caused by the disease.
One of the most common and severe diseases is a brain stroke, in which a large group of neurons simultaneously dies. Creating conditions for the restoration of the affected areas of the brain for the regeneration of the neural network is one of the possible practical applications of our work. I hope this is feasible. Today, researchers from different countries are working on two approaches to restoring normal functioning of the damaged brain. The first is to add, plant new cells in the brain instead of the dead ones, for which to form neurons from the patient's stem cells, which is quite realistic. The second approach is to adapt the surviving part of the human brain to the misfortune that happened to him (the person). Knowledge about the mechanisms of maintaining functional plasticity of the brain is extremely important here. After all, there are still a lot of neurons not affected by the disease – tens of billions. And our task is to ensure that healthy neurons act more actively. We need to find a way to excite their energy, as well as stimulate or reprogram the work of neural networks. I hope that the solution of this problem is feasible in the very near future.
It is clear that the global problems of studying the brain are extremely complex. Several dozen of the world's most advanced laboratories – biochemists and physiologists, geneticists and neurophysiologists - are engaged in the search for a solution... It is encouraging that new, advanced research methods are coming to our aid. For example, extremely sophisticated devices and the latest technologies are increasingly being used for DNA sequencing. Thanks to the use of both existing and proprietary technologies, already today, in one sequencing experiment, we determine the characteristic changes in the genome of hundreds of thousands of individual neurons.
Portal "Eternal youth" http://vechnayamolodost.ru
20.06.2016