Siberia and America – together against cancer
Bioinformatics: successful international cooperation
Dmitry Shtokalo, Researcher, Project curator at ISI SB RAS
"Science in Siberia" No. 38-2013
The relevance of scientific research in the field of medicine has been repeatedly emphasized at various levels, including international organizations such as WHO, government and even business circles. As before, the leading position in the list of the most complex and urgent applied health problems is occupied by the problem of cancer. There are several areas of research in the world, both in the search for new methods of treatment and ways to diagnose this dangerous disease. Extensive international and interdisciplinary cooperation involving the possibilities of information technology inspires optimism and hope that humanity will receive not only reliable means of treatment and diagnosis, but also unravel the nature of cancer.
In recent years, scientists of the A. P. Ershov Institute of Computer Science SB RAS in cooperation with the Saint-Laurent Institute (USA) and other scientific laboratories in the USA and France have joined this kind of research. Encouraging results were recently presented in the July issue of the journal Genome Biology for the current year. Scientists have announced the discovery of the important role of a significant part of DNA in the development of cancer. We are talking about the so-called "dark matter", often ignored by the scientific community. As a result of the conducted joint research, it was found that the sites in the genome that attracted the attention of scientists encoding the so-called vlincRNA (vlincRNA, very long intergenic, non-coding RNAs), activated by elements of retro viruses, are involved in stem cell biology and in the development of cancer. It is important that the artificial suppression of these vlinkRNA molecules leads to the death (apoptosis) of cancer cells.
As a result of reading the human genome in 2003, the rapid development of sequencing technology (determining the sequence of nucleotides in RNA and DNA molecules) and other laboratory methods, a huge amount of information about the genome and its work in various conditions has accumulated in the world's biological databases. Understanding how a living cell executes the program embedded in it through DNA is likely to provide the key to the treatment of many diseases.
A figurative concept of a living computer cell was proposed in the Laboratory of Modeling Complex Systems of the ISI SB RAS under the guidance of Ph.D. Fyodor Alexandrovich Murzin. The cell, according to scientists, processes information flows according to known and unknown algorithms. This analogy makes it possible to more closely apply the rich knowledge of the ISI staff in the creation of artificial information systems for the analysis of living information systems. To confirm the theoretical concept, a connection has been established with experimenters who provide analysts with fresh data and check the results of calculations based on mathematical models in the laboratory. Since 2011, and informally since 2007, the Saint-Laurent Institute, which has a strong experimental base and experience in genomic research, has become a partner of the ISI.
The Saint-Laurent Institute, a non–profit research center for the problems of systemic biology of diseases, specializes in innovative approaches to understanding the molecular genetic mechanisms of chronic diseases. The Institute was founded in 2005 . George St. Laurent Jr., one of the original board members of the Celer Human Genome Decoding project, and George St. Laurent III, an experienced molecular biologist and neurologist. The research activity of the Institute is global and includes projects in Russia, India, Colombia, Brazil, China and the USA. The Saint-Laurent Institute maintains close cooperation with the academic community.
The Saint-Laurent Institute uses high-performance technologies, such as single-molecular transcriptome sequencing (without RNA amplification) and epigenetic DNA sequencing to identify pathways of intermolecular interaction, the violation of which threatens health and increases the risk of disease with aging. Most sequencing technologies (reading the nucleotide sequence of DNA or RNA) artificially amplify (multiply) molecules, which as a result is expressed in an error when measuring their initial number in the cell. This error is transferred to the measurement of the activity of DNA sites that are a "template" for the production of RNA molecules (the set of RNA molecules produced in a cell is called a "transcriptome"). The HelicosTM technology used by the Saint-Laurent Institute can sequence one RNA molecule at a time without requiring its artificial reproduction, which reduces the error in further analysis.
The study of the part of DNA that does not encode a protein and the corresponding non-coding RNA molecules is the strategic direction of the Saint-Laurent Institute originally laid down. Up to 98% of human DNA is called "junk" DNA or "dark matter" because it is not directly involved in protein coding. For many years, "dark matter" has not attracted enough attention from scientists who doubted its important role in the formation of a person and his health. Philipp Kapranov, a leading researcher at the Saint-Laurent Institute, was one of the first to show the large-scale synthesis of non-coding RNAs in human cells in one of his publications in the journal Science back in 2002. Despite this, many scientists still doubt the biological significance of "dark matter", and the concept of "dark matterjunk" DNA has not yet gone out of circulation. In order to understand these important issues, the use of the latest experimental and computational technologies is required.
Thanks to the use of single-molecule sequencing technology to accurately measure the activity level of each section of the human genome, researchers at the Saint-Laurent Institute gain a clearer understanding of gene regulation. The technology makes it possible to identify therapeutic targets for the treatment and diagnosis of diseases. This approach revealed that at least 10% of the DNA from the "dark matter" class is not "junk" at all, but actively participates in the work of stem and cancer cells. Statistical analysis published in the above-mentioned issue of the journal Genome Biology leads to the conclusion that these DNA regions (encoding vlinkRNA) are activated by elements of retro viruses embedded in our genome during evolution.
According to Philip Kapranov, the study of this previously ignored part of the human genome, the establishment of its role in human development and in diseases in the case of disorders, opens a new frontier in science with important applications in medicine. Further investigation of the mechanisms of vlinkRNA functioning is a prerequisite for high-precision diagnostic tests and targeted cancer treatment.
The role of the Institute of Computer Science Systems in cooperation with the Saint-Laurent Institute is to provide mathematical and computational support for experiments, formulate mathematical problems and hypotheses, and analyze the models being developed. The collaboration develops within the framework of the project "Mechanics of Information Processing in living Cells", where the ISI investigates the mechanisms of information transmission through signaling motifs and the spatial structure of RNA. Collaboration with experimenters with the most modern technologies has a very positive effect on the research results of the ISI team. This makes it possible in practice to improve skills in the field of high-performance parallel computing for processing and storing a large volume of formalized scientific data.
New generation sequencing data from the USA continues to arrive at the ISI and return back to experimenters in the form of new biological knowledge. During the period of cooperation in the ISI, more than three terabytes of "raw" RNA and DNA sequencing data of humans, mice, rats and flies were processed. The results of the international collaboration of scientists were published and accepted for publication in 2012-2013 in such well-known publications for molecular biologists and geneticists as BMC Genomics, Molecular Genetics and Genomics, Methods, Genome Biology, Nature Structural & Molecular Biology.
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