From genomics to proteomics, metagenomics and beyond
Life after the genome is just beginning
In the proteomic project, biologists intend to find out how molecular machines workAndrey Vaganov, Independent Newspaper
The First International Scientific and Practical Conference "Postgenomic methods of analysis in biology, laboratory and clinical medicine" was held at the Faculty of Biology of Lomonosov Moscow State University. The conference was organized by the Federal Biomedical Agency, the Research Institute of Physico-Chemical Medicine of the FMBA of Russia, Lomonosov Moscow State University and the Park-Media company. The event was supported by the Ministry of Education and Science of the Russian Federation, the Russian Academy of Medical Sciences, the Siberian Branch of the Russian Academy of Sciences.
Literally every page of the thick volume with the conference program was full of an abundance of academic degrees and titles. What's the matter? What made almost all the leading Russian and many foreign biologists take part in this conference? Here it is necessary to "rewind the film" nine years ago.
"The human genome is a periodic table for biology and medicine," then–US President Bill Clinton said in 2001 at a special press conference dedicated to the completion of sequencing (decoding) of the human genome. (For the implementation of the Human Genome project, in which, according to the most conservative estimates, $ 3 billion was invested, the international organization HUGO – Human Genome Organization was created at one time.) Here it seemed, now it would come, universal happiness, in the sense that we would finally understand exactly how living things function. A new direction of scientific research has also appeared – genomics. But…
The number of genes in the human genome is estimated at about 30 thousand. But the number of proteins from which our body is built and the synthesis of which these genes encode is estimated by the following figures: about 400 thousand – in liver cells, about 2 million – in blood plasma. The structure of proteins, the patterns of their functioning – this is what proteomics does.
Hundreds of thousands and millions of proteins are either the results of recent discoveries, or some kind of confusion. Maybe if you count all the variants of antibodies, you will get values of the order of 10 6, but, according to the generally accepted opinion,
"Human blood plasma contains about 100 different proteins"
(Ya. Kolman, K.-G. Rem, Yu. Wirth, "Visual biochemistry", M., Mir, 2004)
Or do we mean all possible variants of genes and, accordingly, proteins differing by one or several amino acids, but not in one body, but in humanity as a whole? – VM.
"Genomics is an informational material; a mechanism for regulating the implementation of a genetic program," Academician Alexander Archakov emphasized in his report "From the Human Genome project to the Human Proteome project." – Genomics cannot be required to create methods of real medicine; but modern medicine cannot do without knowledge of genomics. Proteomics is the study of proteins, the "working machines" of the genome."
In other words, genomics is a blueprint; proteomics are working molecular machines. Unlike the genome, the proteome is constantly changing. A caterpillar and a butterfly have the same set of genes. But the proteomic (protein) composition is in constant motion. According to Academician Archakov, "proteomics is a situational science; it is not photography, it requires constantly making a film."
In general, it is not for nothing that they are talking about the proteomic challenge today. To feel what biology is "drawn into" after decoding the genome, we can make such a comparison. The number of atoms in the universe is 1080; the number of combinations of proteins is many orders of magnitude more! It is not surprising that from the point of view of modern physical concepts, the appearance of a single protein structure is as incredible as the appearance of a living cell!
I will quote one fragment from my interview with academician Vitaly Goldansky. Our conversation took place in 1999. In the last years of his life, Vitaly Iosifovich was engaged in studying the mechanisms of the earliest stages of biological evolution in the universe. "In a very short time, a polymer chain of certain amino acid links precisely folds into a certain molecular structure, forming exactly this particular protein," he explained. – This structure is unique because it is a very specific way of laying a polymer chain, the only one out of a huge number of all possible ways, which are also about 10,100.
There is even a term widely used in the works on self–assembly of proteins - "Levinthal's paradox". This paradox consists in the fact that it is necessary to understand and explain how, why, in a very short time, the polymer chain finds the right way of laying among such a gigantic number of them. What dynamics can describe the phenomenon of protein self-assembly? From a conventional point of view, these times should have been meaninglessly large, more than the age of the universe."
So the proteomic puzzle leads to some, quite exorbitant, levels of abstraction. But, anyway, in 2010, the international Human Proteome project (under the auspices of the international organization HUPO – Human Proteome Organization) was created as a logical continuation of the Human Genome project. It currently includes six countries, including Russia.
"In the proteomic project, we have to find out how molecular machines work, and no one knows how many of them are molecular machines," emphasizes Academician Archakov. – Each country in the project examines its chromosome (deciphers its proteome). We got the 18th chromosome of the human genome, about 90 diseases are "tied" to it. According to our calculations, the genes of this chromosome encode about 30 thousand proteins. Now there is a competition who will make the first proteome. Russia has a good chance. One copy of a protein per 1000 cells is the sensitivity of our methods today."
But in addition to theoretical and ideological interest, the study of the human proteome (that is, relatively speaking, its protein status) – proteomics has an important applied value. No wonder another name for proteomics is postgenomic technology. One of the most interesting plenary reports on this topic was made by Academician Sergey Shestakov (Lomonosov Moscow State University) – "Metagenomic studies of the human microbiome".
Metagenomics studies the structure, organization and functioning not of individual genomes (human, for example), but of entire genomic communities. Such communities may include the genomes of fungi, viruses, and protists… All in one bottle, as they say.
"A person is considered as a superorganism that possesses a set of genes not only of its own, but also those that live on and in the human body," explains Academician Shestakov. – They interact with each other, and this determines a lot in a person's life. For example, many of them (genomes that do not actually belong to humans. – A.V.) participate in the synthesis of vitamins and neurotransmitters, detoxify, participate in the formation of intestinal mucosa, etc. and so on.".
By the way, in the next 3-4 years, the human gut microbiome can be deciphered completely. To what extent this is a non–trivial achievement - judge for yourself. In the human colon, the biomass of microbes is almost 3.5 kg! 1200 species of bacteria live in the intestine. Five large microbial phylotypes/strains make up 95% of the mass of the intestinal microbiota. The remaining 5% account for eight more phylogroups.
"Throughout a person's life, the microbiome in the intestine is created as if every time anew," says Sergey Shestakov. – But with age, the human microbiome will strive for stability. Each of us has our own microbiome, even homozygous twins who are in the same nutritional conditions. And these microbiomes reflect the state of human health and are a kind of specific biomarker."
Indeed, today, for example, it has been established that rectal cancer may be associated with a change in the composition of bacteria in it. The main mechanism of such influence is participation in the regulation of human gene expression. "Now no human disease can be studied without understanding the role of the human microbiota," Sergey Shestakov is sure. – This opens up completely new paths in metagenomics. The microbiota synthesizes neurotoxins that enter the brain and cause stress. For a long time it was not possible to find the cause of periodontal disease. And it turned out that periodontal disease is a polymicrobial disease."
That is why, according to Academician Shestakov, the individual genetic passport of a person should include information not only about his genes, but also about the genomes of the microbiota living in/on the human body. These microbes contain thousands of genes that are absent in humans, but affect their vital activity. Modern methods of microbial metagenome analysis make it possible to assess the taxonomic affiliation of microbes and to study the gene-metabolic network of an entire ecosystem.
Although metagenomics is a very young science (the first publications appeared in 1998), but a lot of attention is focused on it in the world today. China is among the leading countries in the field of metagenomics. It should be noted that China joined the Human Genome project literally four months before its completion. It was a purely political and organizational step. The Chinese have managed to sequence several hundred thousand nucleotides. Russia had not deciphered any by that time.
We were able to decipher the genome of a representative of the Russian ethnic group only last year. According to academician, Dean of the Faculty of Biology of Moscow State University Mikhail Kirpichnikov, "the very criterion of Russia's possession of human sequencing technology is a marker of technological development." The head of the Federal Medical and Biological Agency Mikhail Kiselyov agrees with him: "The decoding of the genome has opened up completely new opportunities for the development of biomedical science. The scale of implementation is really unpredictable today!" "The main thing is that a genome sequencing system has been created," says Academician Konstantin Scriabin. "This allows us to participate in several international projects now."
"If our country was not ready for the Human Genome project at the time, then the situation with proteomics is completely the opposite," says Academician Alexander Archakov. – Anyway, to start the project. Although the formation of the project is not going smoothly, there are objectors, there are opponents."
Indeed, judging by the reports presented at the conference, the scientific, theoretical and experimental work of Russian scientists is still quite at the world level in some areas of post-genomic research. For example, the director of the Institute of Chemical Biology and Fundamental Medicine of the SB RAS, Academician Valentin Vlasov presented very interesting data on the creation of anti-cancer therapeutic drugs based on nucleic acids. However, the academician had to finish his speech "in a minor": "If we had some kind of chemical industry in our country, then we could move on to production and testing. But, since we do not have a chemical industry, apparently, we will have to turn to foreign firms."
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08.12.2010