29 May 2017

Recipes from the laboratory

University broadcasts health

Arkady Sosnov, "Search" No. 21-2017

Less than two years ago, Professor Raul Gainetdinov of St. Petersburg State University and I discussed the progress of his research on a little-known family of trace amines – potential drug targets for the treatment of brain diseases ("Success Receptors", "Search" No. 29-30, 2015). Then I caught myself thinking that the track record of the interlocutor – associate professor at Duke University (USA), where he worked for 12 years alongside Nobel laureate Bob Lefkowitz, head of the laboratory at the Department of Neuroscience at the Italian Institute of Technology, Professor of Skoltech - is a vivid example of how the grant funding system helps to develop Russian science and involve in she has really talented creators.

Actually, Gainetdinov ended up at St. Petersburg State University thanks to the university grant he won for the creation of a Laboratory of Neurobiology and Molecular Pharmacology. With these funds, he was able to invite several employees and purchase consumables. The study of receptors, which are located in brain structures and control certain physiological functions, organized in the laboratory, was supported by a grant from the Russian Science Foundation, which made it possible to significantly expand the scope of work, establish business contacts with university scientists and purchase equipment. 

By the way, Raul's associate in the study of biogenic amines, Tatiana Sotnikova, received a grant from the Russian Academy of Sciences to support individual research groups in the summer of 2014 – part of his funds was also directed to equipping the laboratory. But this, in general, local success acquired a completely different sound when, in December 2014, St. Petersburg State University won a competition for institutional grants in the priority for the RNF direction "Implementation of complex scientific programs of organizations", presenting a program for the development of translational biomedicine under the leadership of the rector of the University Nikolai Kropachev. 

Comment by the Rector of St. Petersburg State University Professor Nikolai Kropachev:
The development program of St. Petersburg State University provides six priority areas - nanotechnology and materials science, biomedicine and human health, information systems and technologies, ecology and environmental management, social research and technology, management personnel and technology. All of them are interdisciplinary, have deep roots in the history of university science, and are provided with excellent research personnel.
At the same time, biomedicine is one of the most actively developing scientific fields in the world. We considered the translational component of the project to be extremely relevant, that is, the ability to translate the results of scientific developments into medical practice. In many ways, this was the reason for participation in the RNF competition with this topic. 

In February 2015, the Institute of Translational Biomedicine was established at the university, which included the laboratory of Raul Gainetdinov. And since he was actively engaged in the development and promotion of the concept of the institute, in April he was appointed its director. And our new meeting with the energetic professor was no longer devoted to the achievements of his individual laboratory, but to the structure and rules of life of the whole institute, born thanks to an institutional grant of the Russian Academy of Sciences (750 million rubles for five years) – Gainetdinov calls him a collective megagrant and talks with pleasure about the team...

Translational medicine is a trend of the XXI century, although its principles can be seen even in the famous Hippocratic oath. In the modern reading, this is a field of knowledge focused on the accelerated transfer of the results of fundamental research into the field of public health, overcoming interdisciplinary barriers to the introduction of new technologies, data analysis tools, medicines into clinical practice. It is characteristic that it combines a variety of medical disciplines with non–medical ones - economics, law and even linguistics can be useful, for example, when deciphering the recipes of ancient Chinese healers.

For translational biomedicine, this convergence is even more pronounced due to the rapid development and interpenetration of living sciences (biochemistry, bioinformatics, neurobiology, psychophysiology, medical genetics ...). Another key feature of it is the modeling of pathologies in laboratory animals in order to identify the molecular mechanisms of diseases and the search for new human treatments. The same Raul Gainetdinov uses his favorite transgenic mice as models to study diseases such as schizophrenia, depression, Parkinson's disease, attention deficit hyperactivity disorder in children, which opens up fundamentally new pharmacological approaches to their treatment. It is no coincidence that the total renovation of the university vivarium occupies a special place in the project.

Rector's comment:
Of course, the greatest contribution to the development of biomedicine is made by biologists, physicians, specialists in the field of dentistry and medical technologies. But related problems are solved by chemists, sociologists, psychologists, geographers, environmentalists, lawyers, and other scientists of St. Petersburg State University. The information collected by them not only becomes the property of the scientific community, but also (which is extremely important!) it is included in the programs of academic disciplines.

Raul Gainetdinov, who is familiar with the organization of American science from the inside, says that the National Center for the Development of Translational Sciences was first established in the USA in 2011. In the following years, several dozen local translational research institutes funded by him emerged, primarily at large universities. The focus on practical output, on the transfer of innovative technology or medicine to the clinic is so great that it is usually possible to receive a grant for the study of proteins and other high-molecular compounds only if their role in the development of the disease or as targets for medicines is disclosed. A peculiar slogan of these studies was the reduction of the distance from bench to bed – from the laboratory table to the hospital bed.

The peculiarity of St. Petersburg State University is the presence of strong biomedical laboratories of various profiles and subordination. The institute that united them acted as an integrator of several scientific and educational departments as the embodiment of interdisciplinarity. From now on, each of the laboratories included in its composition is focused on the translation of scientific content into medical practice. Their managers are responsible for this – specialists of high international class. All of them, like Gainetdinov, have worked for more than one year (and someone continues to work in parallel) in the West, they received grant support at the university. The level of their scientific qualifications objectively reflects the Hirsch index: from 16 to 64!

In Pavel Pevsner's laboratory, the Center for Algorithmic Biotechnology is engaged in bioinformatics, creating almost the best programs in the world for assembling fragments of genomes after sequencing. Yuri Chernov, Head of the Laboratory of Genomic and Proteomic Research, and his colleagues are studying the biochemical processes underlying Alzheimer's disease and other neurodegenerative diseases, looking for new ways to treat them.

In addition, Chernov, within the framework of the RNF grant, directs the direction "Creation and use of a biobank for a comprehensive biomedical study of the foundations of human health and longevity". And the university biobank, founded even before the establishment of the institute, is a resource center that has no analogues in Russia in terms of equipment with automated reliable and safe cryostores with a capacity of up to 200 thousand samples, a unique genomic sequencer, a station for sample preparation and DNA isolation – just provides translational approaches to biomedicine. Naturally, the institute works closely with him.

And not only Chernov's group, but also Gainetdinov's own laboratory, which, as already mentioned, studies transgenic models of brain diseases. Its employees, in cooperation with psychiatrists, collect and store blood samples of patients with schizophrenia in a biobank for subsequent genetic analysis. Biomaterials of patients with depression, bipolar disorders, drug addiction and other psychiatric diseases will also be stored there.

The fourth laboratory – biological testing of modern drug delivery systems – is headed by Doctor of Chemical Sciences Tatiana Tennikova. Here, pharmacological forms are tested for compatibility with the body in vitro, using the capabilities of the Cell Technology Resource Center. Experiments on animals (in vivo) are carried out both in university collectives and by university partners at the Research Institute of Experimental Medicine of the Russian Academy of Sciences, at the I.P. Pavlov First St. Petersburg State Medical University. 

Another task is also solved by fine molecular biological methods - to ensure targeted delivery of the drug to the affected organ or tissue and controlled disintegration of the nanocapsule. In particular, a smart biodegradable nanoconstruction has been created for the delivery of the latest generation anti-tuberculosis drug perchlozon. According to Tatiana Borisovna, the organization of the institute allowed to strengthen the ties of the laboratory staff with the biobank in the development of modern biochips – diagnostic tests for the analysis of gene mutations accompanying, for example, the pathology of pregnant women.

Mikhail Krasavin, the head of the Laboratory of Chemical Pharmacology, came to the university from the pharmaceutical industry, with which he is still associated. The main interest of his group is the creation of new chemical agents for regulating the functions of a living cell and entire cellular systems based on so–called "small molecules". The breadth of potential therapeutic applications of these biologically active (mainly heterocyclic) compounds with a small molecular weight is impressive: infectious diseases, glaucoma, oncology. There are already practical results: together with foreign researchers, Krasavin found an alternative to fasiglifam, a Japanese drug that was considered the most effective in the treatment of type II diabetes, but turned out to be dangerous due to the revealed liver toxicity.

Mikhail Krasavin's laboratory was the missing link in the structure of the institute, and Raul Gainetdinov is very glad that he managed to involve such a sophisticated chemist-pharmacologist in his team:

– Our animal studies have proved that trace amine receptors can serve as targets for drug effects in certain diseases. And Krasavin found several substances that can be "fired at" targets. We have tested these substances, confirmed their properties and are now patenting them. I hope that as a result we will get fundamentally new medicines. This is a typical translational path from bench to bed.

Even from a cursory list of the functions of the institute's laboratories, one can see how translational biomedicine works. Collection and storage of biological samples of the patient in a biobank – their proteomic, genomic, biochemical analysis – modeling of pathological processes, including on laboratory animals – identification of targets for therapeutic effects – development of drugs and methods of their nanodelivery to the foci of the disease – joint testing of techniques and drugs with clinicians. The scheme starts with the patient and ends with the patient.

It is clear that five laboratories cannot cover all areas of translational medicine. For this, there should be not 40 scientists, but 20 times more, and finances, respectively... And I want to cover it. Therefore, Raul Gainetdinov proposed to attract three more groups of researchers to the university, as associates. 

Alan Kaluev, who heads the Laboratory of Biological Psychiatry, is engaged in modeling diseases of the central nervous system and rapid screening of new neuroactive drugs, only not on laboratory mice, but on a more economical model – aquarium fish danio rerio (for reference: the cost of one mouse is $ 25, one fish is 50 cents). And, of course, it is economically important that Kaluev still has a couple of grants from other scientific foundations. 

Oleg Shuplyakov, professor at the Karolinska Institute in Sweden, studies the molecular mechanisms of neurodegeneration in parkinsonism. He also came to the institute not as a poor relative, but with an RNF grant. The youngest of the heads of laboratories, 37-year-old Pavel Musienko, models new methods of restoring spinal cord functions using neuroprostheses on rats. According to his resume, he fits perfectly into the collective portrait of the institute's head teachers: he worked for a long time in Switzerland, published in Science and Nature. The equipment for his laboratory is purchased at the expense of the university. Moreover, he was granted a grant of a young professor of St. Petersburg State University – and this is a salary plus the opportunity to hire two employees.

An integral part of the program for the development of translational biomedicine at St. Petersburg State University was the creation of a vivarium with funds from the RNF grant that meets strict international requirements: clean rooms, cells with individual ventilation, sterile operating rooms...

– The university planned to purchase a small blocky American vivarium for the maintenance of transgenic animals, – Raul Gainetdinov began a tour for a "Search" through a compact building still clad in forests. – But, thanks to import substitution, we were able to purchase a modern vivarium based on a domestic unit, with American technical stuffing. And the money was left even for the re-equipment of the old vivarium. And the university carries out exterior finishing works at the expense of extra-budgetary funds. 

The vivarium is already functioning, the mice of six transgenic breeds living in it honestly serve science. It is located in the courtyard of the ensemble of Twelve colleges, not far from the monument to the Experimental Cat, an honored participant in many experiments since the time of Academician I. Pavlov. Gainetdinov, who dotes on his transgenic wards, dreams of putting a monument to a Mouse in front of the vivarium.

The institute does not have a separate building yet – some laboratories are located in Peterhof, another on Vasilyevsky Island, premises are being renovated for the third, but Raul Gainetdinov is sure that the research team is united not by walls, but by ideas that are born in discussions of publications and reports at regular seminars, including annual field seminars. The Institute at St. Petersburg State University is formed on the principle of the Boston Broad Institute, a famous interdisciplinary biomedical center with powerful partners in the person of the Massachusetts Institute of Technology, Harvard and five research hospitals in Boston. The center has only 11 own laboratories, but 195 associates and about 1,000 employees. Broad Institute was founded in 2004 with a donation of $100 million from philanthropists Eli and Edith Broad and has now increased its budget to $280 million a year, 55% of which are state grants.

– Our research areas are similar – genomics, bioinformatics, biomedicine. We are creating the same research network as them, their technological platforms are comparable to the resource centers of our university. We started with a grant of 750 million rubles, that is, about $ 12 million, which is eight times less than the initial investment in the Broad Institute. But since today it is the most powerful biomedical institute in the world, it is already good to be 1/8 part of a giant! – Gainetdinov argues.

– After all, you are still noticeably inferior to them in terms of the number of partners...

– For the maintenance of serious laboratories, in which researchers would interact directly with clinicians, additional sources of funding are needed. Including budget ones, – the interlocutor states. – On the other hand, as a pharmacologist, I know that ten years pass from birth to clinical use of the drug. So I regard the creation of our institute as the first step, which will logically be followed by the optimization of existing and the emergence of new structures aimed at translating biomedical research into practice.

Meanwhile, a scientific and educational cluster "Translational Medicine" has been created in St. Petersburg on the basis of the Northwest Federal Medical Research Center named after V.A.Almazov, together with the leading universities of the city engaged in the development of drugs and medical equipment. Oddly enough, neither the St. Petersburg State University with its biomedical institute, which was created six months earlier, is listed as a participant or a partner. Are there really interdepartmental barriers growing inside translational medicine?.. 

Rector's comment:
The formation of the cluster and our Institute of translational biomedicine went virtually parallel. The tasks of these structures are also similar. With this in mind, we are ready to cooperate and are open to proposals for the development of joint projects in the field of translational research from all interested parties.

The ideal complex that allows you to quickly transfer knowledge from science to practice was spied by Mikhail Moshkin, Doctor of Biological Sciences from the Institute of Cytology and Genetics of the SB RAS at the Japanese Tohoku University in Sendai. There, at the Faculty of Dentistry, the clinic is connected by a passage to the laboratory building. In one wing they treat people, in the other they conduct research, for example, they study painful sensations in the chewing muscles on mice, look for new diagnostic tools or create new materials for prosthetics. At the same time, masters and postgraduates work both in laboratories and in the clinic.

Educational activities in the field of translational biomedicine at the university are conducted both in the format of lectures and seminars for students, and along the line from the supervisor to the graduate student. Professor Gainetdinov, for example, has five of them. At the same time, building the structure of the institute, the university is also engaged in another kind of construction – the formation of interdisciplinary educational programs covering legal, economic, psychological, ethical aspects of modern biomedicine.

Rector's comment:
The indisputable competitive advantage of St. Petersburg State University as a classical university is the possibility of interaction of specialists from various fields of knowledge. So, there are a number of problems in biomedicine, the solution of which requires improvement of the current legal framework. For example, to implement another large-scale university project "Russian Genomes", it was necessary to develop a form of consent of donors of biological materials for their participation in research. This document explains to the project participants the essence of the research, the rights and obligations of donors and the responsibility of researchers. When developing it, the requirements of international law, the Constitution of the Russian Federation, federal laws on personal data, on the protection of citizens' health, etc., as well as existing ethical standards in this area were taken into account.

This is just one example – the field for cooperation between biomedics and lawyers is quite wide. We can recall the Association of Medical Law of St. Petersburg, established in 1999 on the basis of St. Petersburg State University, which has been a member of the World Association of Medical Law since 2011. In addition, since 2002, the University has annually held the conference "Medicine and Law in the XXI century", which has become an authoritative platform for discussing the most complex issues of medical law and bioethics. Finally, the first Master's program in medical law in Russia has been opened and successfully implemented at St. Petersburg State University.

The final part of our conversation with Gainetdinov took place in his small office in the historic building of the Twelve Colleges. I reminded him that, according to the conditions of the RNF, at the end of the grant period by 2019, the university should have five world-class biomedical laboratories, and asked what are the chances of reaching this level. The director of the Institute answered this fateful question, strictly relying on the figures:

– Over the past two years, we have published 162 articles with a total impact factor of 741. Most of the groups were noted for publications in one or another edition of Science and Nature. If we assume that the impact factor, for example, is Science 35, then this is about 20 publications of the highest level. That is, in terms of the number and quality of publications, we already exceed all the requirements several times today. It is clear that some work is being carried out in cooperation with laboratories in the West. But the main thing is that world-class laboratories are really operating at our university, expanding the range of research and partnerships.

After that, based on his professional experience, he considered it necessary to note the main thing, in his opinion, the dignity of grants from the Russian Science Foundation:

– They provide an opportunity for full-fledged scientific activity in Russia. Receiving a large grant from the Russian Academy of Sciences completed equipping my laboratory according to the best international standards. Without the St. Petersburg State University and the Russian Academy of Sciences, my return to my homeland and transformation from a "guest performer" into a full-fledged Russian scientist would have been impossible. As for colleagues at the institute who continue to work for two or even three "scientific houses", I hope that if things continue to go well with us, some of them will follow my example.

Rector's comment:
How will the activities of the Institute of Translational Biomedicine develop after the grant expires? I am sure that it is as successful as today. Grant funding gave us the opportunity to create a base – personnel, infrastructure, purchase the necessary equipment. On this basis, research has been launched, already the first results of which allow employees and teams to submit weighty applications for competitions of scientific foundations, win grants and thereby confirm their viability. In general, when creating new research units, the university always sets a key task for them, which is to ensure self–financing and sustainable development, whether through a grant from the Russian Academy of Sciences, mega grants from the Ministry of Education and Science or its own funding competitions. And this is possible only when obtaining world-class scientific results.

Portal "Eternal youth" http://vechnayamolodost.ru  29.05.2017

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