At the membrane level
Marina Muravyeva, STRF.ruPhoto: Alexey Nikolsky, for STRF.ru
There is a rapid growth of research on membrane proteins in the world, on which the most important processes in the cell depend and which serve as targets for almost 70% of drugs existing on the market today.
The Institute of Bioorganic Chemistry of the Russian Academy of Sciences (IBC RAS) has been working on membrane proteins since the mid-1970s. This direction was formed then under the leadership of the director of the Institute, Academician Yuri Ovchinnikov, in six or seven laboratories at once – different aspects of the problem were studied in parallel. During the years of perestroika, most scientific groups actually broke up. And only in the laboratory (since mid–2007 - department) of structural biology of Alexander Arsenyev, the work related to membrane proteins, despite all the difficulties, continued. A new impetus to the development of the direction that was once a priority for the institute was given by the victory in the competition of the Federal Scientific and Technical Center in 2005 and the receipt of a grant of 120 million rubles. For two years, the staff of Professor Arsenyev's laboratory, together with colleagues from IBH, as well as from other academic institutions and universities, carried out a comprehensive project to create a universal postgenomic technology for the development of new generation drugs.
The Department of Structural Biology consists of three laboratories: biomolecular NMR spectroscopy (Head Alexander Arsenyev), modeling of biomolecular systems (Roman Efremov) and optical spectroscopy and microscopy of biomolecules (Alexey Feofanov). The department employs about 25 researchers and the same number of graduate students and undergraduates.
Scientific RenaissanceThis is how Professor Arsenyev speaks about the period of participation in the FCNTP.
"Thanks to this project, we gained invaluable experience, felt a taste for work," the scientist admits. – A large grant allowed us to get away from a lot of small ones, Alexander Arsenyev: "Thanks to the FCNTP project, we gained invaluable experience, felt a taste for work. A large grant (120 million rubles) made it possible to get away from a lot of small topics that were previously dealt with with very modest funds from the RFBR and some foreign funds,"those that were previously dealt with with very modest funds from the RFBR and some foreign funds. And here we concentrated on one big serious problem. Everything was subordinated to her decision, including the new organization of work."
When starting the project, the first thing they did was abandon the usual practice, when each participant of the project is allocated a part of the funding, some task is assigned, and after six months or a year, when it's time for reports, it turns out who did what. In this case, the directions of research were immediately identified, for each of them
we have secured the coordinators. Once a week, all the project executors gathered, discussed the results obtained and outlined current tasks.
"We have seen from our own experience that the new system of organization of science and scientific work can work," says Roman Efremov, head of the Laboratory for Modeling Biomolecular Systems of the Department of Structural Biology of the IBH RAS. – The project has shown that with sufficient funding (although not very large by international standards), it is possible to solve urgent and serious scientific problems, attract first–class specialists for this - they are still in Russia, not all have left. We managed to gather like–minded people, enthusiasts - all those who agreed to work hard. And the pace was set very high. But the results are also impressive."
Antibiotics from spidersThe project to create a universal postgenomic technology was carried out in four directions, united by a common strategic task – the study of membrane proteins and peptides.
It is quite difficult to study this class of objects: proteins are located in the membrane, so it is extremely problematic to obtain information about their dynamics, structure, functions, etc. Using instrumental methods. Special approaches are needed. The project participants used modern methods of genetic and protein engineering, protein chemistry, structural biology, chemical synthesis and high-performance computing technologies in a complex.
The researchers focused on several types of membrane proteins that are drug targets: antimicrobial peptides (protein-based antibiotics), ion channels and their fragments, integral membrane receptors, and some others. The choice of the studied objects is quite justified. For example, many cardiovascular, mental, oncological and other diseases are associated with a violation of ion exchange, which is responsible for conducting nerve impulses. The development of peptide antibiotics is also very relevant, in which scientists from the Department of Structural Biology have already achieved significant results. It is obvious that antibiotics of the second or third generation have lost their effectiveness: microbes have long developed resistance to them. Therefore, new molecules are needed, for example, peptide ones. Based on the data of Russian researchers who analyzed the genome of spider glands (responsible for the production of venom) a few years ago, IBH scientists found some peptides that could potentially become antimicrobial (antibiotics).
"We have found over 20 unique peptides in spider venoms that can become the basis for future medicines," says Alexander Arsenyev. – We needed to understand how these peptides interact with the membrane, what their structure is. The problem is that, on the one hand, peptides fight bacteria, on the other, cause hemolysis (destruction of blood cells). As a result, we were able to create molecules with reduced hemolytic activity and increased antimicrobial activity. In fact, we have made a molecular design of new biologically active compounds based on natural analogues: we have removed unnecessary functions and strengthened the necessary ones."
By the way, during one of the experiments to test the hemolytic action of peptides, students and graduate students of the Department of Structural Biology became voluntary donors, that is, they literally "paid with blood" for scientific results.
After the completion of the FCNTP project, scientists from the Department of Structural Biology of the IBH RAS continue to work in the field of postgenomic technologies. As they say, during the execution of the project, they have accumulated so much material that they can deal with it for another two or three years, analyze it.
Medicines with the exact addressCurrently, researchers are developing drugs for the treatment of neurodegenerative and oncological diseases and are conducting their search within the framework of three main areas affecting ion channels, protein kinase and G-protein coupled receptors.
The initial stage of cancer is due to the fact that some chemical signals coming into the cell from the outside stimulate its constant division. But to transmit a signal inside the cell, it is necessary that two tyrosine kinase receptor molecules interact and unite (their dimerization occurred) – they do not work alone. Scientists of the Department of Structural Biology became interested in how their complex is formed, and began to determine the spatial structure of these proteins. Knowing it, you can find out the mechanisms of their work and try to create a certain molecule that will interfere with the formation of a protein complex and thereby stop the growth of a tumor. "Our goal is to create interesting molecules that can become medicines in the future," explains Alexander Arsenyev. – Existing ones affect the cell either from the outside or by getting inside it. We are developing molecules that will work at the level of the cell membrane. This is the first task – to prove the possibility of such an approach and demonstrate new molecules in action. Targeted anti-cancer drugs already exist. But, unfortunately, there are not enough of them yet. In addition, they are very non-selective, toxic to the body and long-term rehabilitation is required after therapy. Therefore, work in this direction is more than relevant."
The developments of the structural biology department are ready to support large pharmaceutical companies. The collaboration of scientists with the Swiss firm Novartis Pharma, which has given a grant for experimental studies of the spatial structure of G-protein coupled receptors, has been going on for the third year. Russian investors are also showing interest. One company expressed its willingness to invest a million dollars. Negotiations are underway at the moment.
In addition to the funds of partners, the Department of Structural Biology conducts research on grants from the Russian Foundation for Basic Research, some other funds, as well as funds from the program of the Presidium of the Russian Academy of Sciences "Molecular and Cellular Biology", under which four million rubles are allocated annually for basic research for five years.
Ideas, personnel, devices…Participation in the FCNTP allowed the Department of Structural Biology to make significant progress in the research of membrane proteins and peptides.
The acquired modern equipment played an important role in this. In terms of technical equipment, only some laboratories in Russia can be compared with this department. At the same time, Alexander Arsenyev admits: "We cannot say that we are unique: this is a normal situation at the level of a good Western university, be it Zurich, London, Harvard, Milan, etc. But for Russian conditions, of course, this is very rare."
Professors Arsenyev and Efremov arrange a short tour of the laboratory, show the latest acquisitions. Among them is the only confocal microscope in Russia with an ultra–high spatial resolution (100 nanometers), with which it is possible to observe intracellular processes, obtaining a very clear three-dimensional image.
The computing resources of the laboratory are also impressive. They are based on four high-performance multiprocessor clusters, which are necessary for calculations when creating biologically active molecules. In addition, employees of the Structural Biology Department have access to computing resources of the Interdepartmental Supercomputer Center of the Russian Academy of Sciences.
With undisguised pride, Alexander Arsenyev demonstrated NMR spectrometers installed in a new laboratory building (nuclear magnetic resonance is a very promising method that allows us to study the spatial structure and dynamics of macromolecules at the atomic level under conditions as close as possible to physiological ones). Two years ago, there was an abandoned warehouse in this room with rusty metal that had accumulated over 20 years. The room was renovated, and the staff of the Structural biology department launched new equipment. The smallest NMR spectrometer at 600 MHz costs about one and a half million euros, the largest (800 MHz) - about five million. Funds were allocated through the RAS and the Ministry of Education and Science.
Looking around the laboratory, it was nice to see young faces. Contrary to expectations, the Structural Biology department did not complain about the lack of personnel, difficulties in attracting young people. Students start working here from the third or fourth year, mainly from Moscow State University, MEPhI and MIPT (the latter has a basic department headed by Professor Arsenyev). Many of them stay in the laboratory after graduation.
"The problem is that we cannot officially hire even the most talented and promising young specialists," says Alexander Arsenyev. – There is a reduction of staff in the institutes, there are no free rates. Recently it became known that four of our young candidates of sciences received presidential grants in the section “Biology, agricultural sciences and technologies". (In total, 60 such grants were awarded in Russia. It turns out that almost 7% of young talented candidates of sciences of Russia in the field of biology work in our department.) While they are working for the grant. But this is all temporary, not only money is important to people, status, housing, social status are important to them, it is important to be listed in the structure of a scientific institution. We are afraid that they will simply leave for the West. Our specialists are ready to be accepted in the best laboratories in the world, for example, not so long ago a graduate student defended her PhD and left for a three-month internship in Sweden, it was impossible to get a staff unit for her at the institute. Just a month later, she was offered a three-year contract at Stockholm University. She agreed. And it happens all the time. Generally speaking, it's a terrible shame to train specialists for the world's leading laboratories from year to year."
At the same time, foreigners also show interest in the Department of Structural Biology of the IBH RAS, trusting the qualifications of its employees. Moreover, there could be a queue of those wishing to get here. Especially many Indians and Chinese want to study and train here. But you can accept them only if you have a grant. So, a student has recently arrived from the same Sweden and will be doing his thesis for six months.
Despite all the difficulties, Alexander Arsenyev and his colleagues are optimistic about the future: "In general, it's a sin for us to complain. The equipment is comparable to Western, the ideas are also not worse, the qualifications are high. But life is more expensive, salaries are lower. Therefore, we would like our employees' incomes to be at the European level."
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14.04.2008