14 June 2016

Accounting with calculation

Decoding the human proteome will help defeat diseases

archakov.jpgAndrey Subbotin, "Search" No. 24-2016

The scientific director of the V.N. Orekhovich Research Institute of Biomedical Chemistry, Academician Alexander Archakov, told about the International Project "Human Proteome" and the participation of Russian scientists in it at a meeting of the Presidium of the Russian Academy of Sciences.

The human proteome is a collection of proteins in the body. The International Human Proteome Project was launched in September 2010 in Sydney, becoming a continuation of the Human Genome project. 

Russia did not participate in the latter, but it became one of the six initiator countries (the Republic of Korea, the USA, the Russian Federation, Sweden, Canada and Iran) of an international proteomic project, the goal of which is even more ambitious: to measure the content of gene expression products – proteins – in the human body. It is assumed that this knowledge will open up new horizons in the diagnosis and treatment of diseases.

– Genomics is a science that provides information about human health and the statistical probability of the occurrence of a disease. The influence of genes is only a "part of the pie" called "disease," A. Archakov explained. – The gene is a carrier of information. Protein is a working molecular machine that performs the functions of metabolism, energy conversion, signal transmission, and catalysis of biochemical reactions. Proteins also perform protective, regulatory and structural functions, participate in the transport of substances and in ensuring the motor activity of the body.

The main goal of the Human Genome project is to establish the sequence of elements that make up the genome of homo sapience. This is an informational task. The main goal of the Human Proteome project is to inventory the proteins of the human body and to clarify the interactions between them. This is an analytical task. The fundamental difference between genomics and proteomics can be shown by a simple example: a caterpillar and a butterfly. They have one genome, different proteomes, that is, different parts of it are read with one genome.

The academician stressed that many experts doubt that genomics will solve all the problems of medicine. This is obvious from the comparison of identical twins: for example, both will have psoriasis (here the influence of the gene is strong), and both do not have to suffer from cancer or multiple sclerosis (according to the oncoline, the genomic influence is very weak).

In general, A. Archakov noted, there are no two individuals in the world with exactly the same metabolism, each person differs from the other by 0.1-0.2% of the genome (this is only 20-40 genes). Perhaps 3x10 to the sixth degree of genome variants or 10 to the 2 millionth degree of combinations of their variants. For comparison, the number of atoms in the universe is 10 to the 80th power. The number of proteoforms (types of proteins) has not yet been determined. "There are a lot of protein variants in the body," the academician said. "We know how many genes we have, but we still don't know how many proteins." It is difficult to identify proteins, because even the plasma proteome of a healthy person is constantly changing.

Alexander Archakov said that among the approaches adopted by the international community to the study of the proteome, one of the most successfully developing was the chromosome- or gene-centric approach, in which the results of protein analysis are mapped to the corresponding protein-coding genes of a certain chromosome. To date, the project involves more than 20 countries (USA, Canada, Republic of Korea, China, etc.), whose efforts are aimed at measuring proteins encoded by 25 human chromosomes (22 somatic, 2 sex chromosomes – X and Y, as well as the mitochondrial chromosome). The Russian part of the project is to determine the content of proteins encoded by the genes of human chromosome No. 18, selected according to the optimal ratio of the number of protein-coding genes and their medical significance.

According to the roadmap of the project approved by the international consortium, the ultimate goal of the Russian part is to determine the size of the proteome of chromosome No. 18 in three types of biological material – human liver cells, hepatocellular carcinoma HepG2 cell line and blood plasma. In the first five years of the Human Proteome project, through the use of modern mass spectrometric methods, Russian scientists achieved the best coverage of proteins encoded by a single chromosome.

Academician Archakov expressed special gratitude for the cooperation in the Human Proteome program to colleagues from the Institute of Biomedical Chemistry of the Russian Academy of Sciences, the Institute of Bioorganic Chemistry of the Russian Academy of Sciences, the Nanotechnology-MDT Company, the Bioengineering Center, the Institute of Marine Biology of the Far Eastern Branch of the Russian Academy of Sciences, the Institute of Biomedical Problems of the Russian Academy of Sciences and the Research Institute of Physico-Chemical Medicine.

Alexander Ivanovich answered the questions of colleagues. Academician Mikhail Ugryumov asked him to specify the main tasks of fundamental biology in medicine and clinical medicine, which this approach can solve as a tool.

– All new sciences: genomics, transcriptomics, proteomics and metabolomics – generate fundamental knowledge and contribute to the development of technologies. At the same time, they create a market. For example, genomics is a profitable business. The volume of the global genomic market is about $ 200 billion a year, and basically all countries work on American devices, improving the US economy," Alexander Archakov said.

He also recalled the latest achievement in genomics – reading single RNA or DNA molecules. "This is a completely different level, allowing us to move away from the average indicators in research," A. Archakov said.

The discussion began with a speech by the Director of the Institute of Bioorganic Chemistry. academicians M.M.Shemyakin and Yu.A.Ovchinnikov academician Vadim Ivanov. He spoke about the biodiversity of peptides and the size of the human proteome and peptidome. Each protein undergoes transformations in the process of vital activity, is destroyed by proteases into smaller fragments – peptides. Peptides are hormones, antibiotics, toxins, signaling molecules, immune regulators... The genome contains about 20,500 genes. The proteome is millions of proteins, and the peptide is hundreds of millions of peptides.

– Peptides are a promising class of medical biomarkers, the "dark matter" of the human proteome, – V. Ivanov believes. – Today, 3342 peptide fragments of 366 proteins have been identified in human blood serum.

By the way, the academician noted, only one tenth of the cells in the human gut microbiota belong to humans, and our genome is 100 times smaller than the total genome of the intestinal microflora.

According to Academician Alexander Aseev, Chairman of the Siberian Branch of the Russian Academy of Sciences, "physicists should invest in the creation of modern analytical tools." Alexander Leonidovich told the members of the presidium about the contribution of Siberian scientists to the study of the human proteome.

Thus, the development of technology by specialists of the Institute of Semiconductor Physics SB RAS and the creation of ultrathin silicon-on-insulator structures made it possible to make ultra-sensitive sensors for biological molecules. A prototype of a nanowire biomolecule sensor with a liquid microcell and an electronic chip with a sensitivity of about

1 femtomole, well-proven in work.

Academician Mikhail Ugryumov was surprised that the term "epigenetics" was not mentioned at the presidium meeting, although, according to him, it was about it.

– The approach we are talking about is suitable for solving both fundamental and key applied problems. Today it is obvious that the genetic program is under the control of intercellular signals, – M. Ugryumov said. – This ultimately determines the ability of the human body to adapt to changing environmental conditions. The study of such mechanisms is a fundamental task.

According to Academician Vladimir Chekhonin, methods are emerging in science that allow analyzing pathological processes and their basis on a completely different level.

– Today, no one is talking about finding a specific marker for a particular disease. They talk about the spectrum of proteins associated with a particular pathological process," he noted.

Andrey Lisitsa, Director of the V.N.Orekhovich Research Institute of Biomedical Chemistry, Corresponding Member of the Russian Academy of Sciences, pointed out the possibility of supplementing the task of early detection of diseases with health diagnostics.

– The participation of our scientists in the Human Proteome project promises interesting scientific results, – said Andrey Valeryevich. – A high-precision representation of the organism in the form of a digital image is necessary. Digital mapping opens up the possibility to carry out diagnostics according to the profile of biomarkers, which allows us to talk about postgenomic medicine as a new relevant direction of fundamental research.

Academician Anatoly Grigoriev called the project very important, but did not agree with the prevailing opinion that the medicine of the future is limited to genomics or proteomics.

– The future of medicine lies in the connection of these new sciences with the science that is traditionally called "physiology". The science that deals with the regulation of functions will always remain the most modern," insists the Vice President of the Russian Academy of Sciences.

Portal "Eternal youth" http://vechnayamolodost.ru  14.06.2016

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