Micro-RNAs, omnipresent and omnipotent
The cancer will be under control
"Science in Siberia" No. 44-2013
Prepared by A. Sobolevsky. Photo of the author
"In the XVIII century, all meteorites found in France were delivered to the Royal Academy of Sciences. And its president, the famous chemist Antoine Lavoisier, imposed an unambiguous resolution: "Stones cannot fall from the sky, because there are no stones in the sky" (which did not prevent him from discovering oxygen). microRNAs are the same "heavenly stones" that didn't seem to exist until recently."
With these words, Doctor of Biological Sciences Nikolai Nikolaevich Kolesnikov from the Institute of Molecular and Cellular Biology SB RAS began a story about a discovery that could rid humanity of one of the most dangerous ailments.
If oncological diseases are suspected, such diagnostic methods are still used in our country to this day that they immediately detect the 3rd or already the 4th stage. Physical examination, ultrasound, MRI, biochemical markers make it possible to diagnose cancer more accurately, but the trouble is that these methods begin to be used when the patient feels like such, began to complain of pain and discomfort. The solution to the problem may be in detecting the disease at an early stage and, accordingly, obtaining reliable markers for this. Then it will be possible to screen the population for the entire spectrum of oncological diseases, whereas now there are mass examinations for breast tumors in women and prostate tumors in men, and the latter are trying to avoid this.
Twenty years laterIf broad and reliable screening is the most urgent task of practical medicine, then the role of fundamental science is that it undertakes the development of new directions.
The discovery of microRNA and its functions was, without exaggeration, a giant breakthrough. It was found on traditional laboratory objects, nematode and drosophila: as you can see, they should not be treated with disdain. And it happened just 20 years ago, in 1993, in the laboratory of Victor Ambrose (Dartmouth Medical School, Great Britain). And after another 10 years, it became clear that these molecules are not only connected with the processes of cell development and the whole organism – they are omnipresent, they are in the cell and intercellular space, there are many of them, they are different...
microRNAs are found even in viruses! Moreover, the virus acts on the cell with its microRNAs, suppressing it, and then reproduces unhindered. According to academician Igor Fedorovich Zhimulev, microRNA serves the virus as a switch of the hereditary apparatus, "sitting down" on the products of the genes of a normal cell, after which the cell synthesizes hundreds of new viruses and dies. microRNAs are many-sided and universal. If we talk about the human body, then, starting from the embryonic stage, they direct the processes of cellular differentiation, as if deciding which cells to form kidney tissue, and which – spinal cord. microRNAs control both growth, aging, and cell death.
In 2001, microRNA was recognized as the "molecule of the year" by the journal Science. For 12 years, the number of publications on this topic has exceeded one million. Science has received information about fundamentally new regulators of gene activity. If earlier it was believed that genes are regulated mainly by transcription factors, now it is clear that there is a powerful post-transcription segment, this is exactly what microRNA is.
Back in 1953, Watson and Crick, later Nobel laureates, established the structure of DNA, which marked the beginning of the era of molecular biology (genetics was being smashed in our country at that time). The fundamental principle of complementarity of bases in two DNA strands has turned out to be universal and is used in the processes of replication and transcription. Evolution does not throw anything away, but uses it in new variants, as it turned out, in the case of microRNAs. In most cases, microRNAs are short chains of 22 nucleotides, which, sitting on regulatory sites of genes, block the synthesis of a particular protein. At the same time, one microRNA can regulate the work of hundreds of genes, and almost 80% of the human genome is under their regulation. Conversely, one gene can be regulated by dozens of microRNAs, resulting in counter combinatorics.
It is these mechanisms that can explain the differences (in the regulatory potentials of genomes) between humans and chimpanzees, whose DNA matches 98%. It's like melodies extracted from the same instruments by different musicians. microRNAs underlie the differences in the reactions of the brain of men and women, the characteristics of the organisms of human races and nationalities, and, importantly for us, microRNA disorders form the pictures of almost all pathologies: cardiovascular, oncological, diabetes, obesity...
Our body contains 10-14 cells. Previously, it was believed that RNA does not go beyond the cell, and hormones are responsible for intercellular information connections. But it turned out that the cells address each other tiny vesicles, vesicles (for the discovery of which the 2013 Nobel Prize was awarded). And the vesicles contain genetic information in the form of the same microRNAs. Cells and tissues exchange address signals not only at the gross hormonal level, but also at a more subtle level, and this is a two-way communication. In response to the "command" of some cells, another reaction can be not only its execution, but also a counter-response. And finally, those microorganisms that live and thrive in our tissues and organs can also affect gene expression through their micro-RNAs. So the expression "a person is what he eats" from a philosophical metaphor becomes literal, since the microflora is formed largely due to nutrition. For example, there is a microRNA in rice that is involved in the metabolism of an animal cell. Obesity and other nutrition-related pathologies can be modulated by microRNAs entering the body. It seems fantastic, but it is already a reality, although research in this direction is just beginning.
A paradigm, but not a panaceaIn the field of genomics, as well as in the study of intercellular (and in general, biological) interactions in the body due to the understanding of the functions of microRNAs, a paradigm shift has occurred.
I read the latest release for June 2013: due to high-performance sequencing methods, 1800 microRNAs have already been isolated in the human genome, and this is not the limit. But let's remember that one microRNA can regulate up to a hundred genes: the number of combinations increases, and they add up to a thin hierarchical system, since we also know the feedback, that is, programming by microRNA genes. This knowledge already makes it possible to solve such a problem as stem cell reprogramming: in 2011, a complex of only five microRNAs gave way to 30% of transformed cells. As for oncological diseases, finding the key molecule responsible for malignant cell growth provides a fundamental opportunity to suppress the process and reverse it. Studies and experiments by a group of authors from Yale University (USA) in 2012 showed that when injected into mice with the help of nanoparticles, only one, but successfully selected microRNA, it is possible to remove the development of lymphoma in two days.
At our institute, we have set ourselves two goals. The first is to understand the role of microRNAs in the mechanism of carcinogenesis, it is very difficult and only works in a wide community. The second task is of a more practical plan: to create a diagnostic method that allows to distinguish benign formations from malignant ones at an early stage, so as not to expose the patient to unnecessary procedures and to facilitate his existence at least psychologically. When a person does not know what is happening to him, it is painful. At the same time, I would like to share a reasonable skepticism: may some colleagues forgive me, but I do not believe in loud statements that, they say, methods of reliable early diagnosis of oncological diseases have already been found today. Even individual ones, like breast cancer or prostate adenoma. I say this because I have experienced similar illusions myself, and then examined the pitfalls along the way. We go to the diagnostics of the early stages slowly and in stages, through the study of blood plasma and the isolation from it of the very vesicles (or exosomes) that contain the microRNAs of interest to us. But then there is the problem of determining the norm, the range of statistical fluctuations and the obviously critical level of these microRNAs. There is a lot of work ahead to collect, process information, systematize and evaluate it.
Abroad will not help usI will note that our institute can not afford any kind of research – for prosaic financial reasons.
The device, which costs five million rubles, may require consumables for another 20. We have followed the path of cooperation, the path of using techniques and equipment that are minimal in price and satisfactory in performance. Thus, the Novosibirsk company Vector-Best, in close cooperation with which our work is carried out, produces almost all the necessary reagents, starting with special primers for the identification of micro-RNA and ending with sets of reagents for expression. The company "Biorad" (USA) gave us a CFX device on loan, and for two years in advance.
We cannot embrace the immensity and have focused on three objects: thyroid, brain and breast tumors. We work in close cooperation with the 1st Novosibirsk City Hospital, the Research Institute of Traumatology and Orthopedics, the Clinic of Neurosurgery, the Novosibirsk Regional Dispensary. Only now, after two years of painstaking work, it gradually becomes clear what degree of expression of which microRNA can be associated with a specific disease. And here no "abroad" will help us. Firstly, our patient will not go abroad for an analysis, and secondly, any cancer has regional characteristics. We plan to create not just diagnostic panels, but adapted to certain territories. And this goal seems achievable in a fairly close perspective. Our specialists have already made diagnoses based on the peak contents of certain microRNAs, and these diagnoses were confirmed by traditional methods.
The problem of cancer is the problem of the first cell to embark on the path of uncontrolled division. The question is how to find her. Today, there are already devices that allow you to determine the absolute amount of microRNAs in a minimum physical size, for example, in a microliter volume of blood. Such a device costs 5.5 million rubles. But the question is not only in its acquisition, but also in the training of specialists. Shots! I agree with Academician I. F. Zhimulev, who insists on opening a department of molecular genetics at the NSU at the Faculty of Natural Sciences or at the medical faculty. In our country, we have seen centers literally stuffed with the most modern devices worth hundreds of millions... who have no one to work for. It's not just about training practical researchers, but also about ordinary doctors knowing what a gene is and what a microRNA is. New technologies that are already working today require a new generation of personnel. Otherwise, Russia risks remaining on the periphery of this breakthrough.
Portal "Eternal youth" http://vechnayamolodost.ru07.11.2013