Ulcer less
The development of regenerative medicine has received a powerful impetus
Yuri Drize, "Search"
Recently, the III National Congress on Regenerative Medicine was held at the Lomonosov Moscow University. Among dozens of interesting reports, the presentation of scientists from the St. Petersburg Institute of Cytology (INC RAS) stood out. About 30 specialists arrived from the university in the capital, who presented nine reports. Moreover, two of them are plenary of Academician N. Nikolsky and corresponding member of the Russian Academy of Sciences A.Tomilina. It seems that the activity of the residents of St. Petersburg did not surprise the forum participants: The Institute has been conducting research in the field of cell biology and the creation of biomedical cell products for almost a third of a century and occupies a leading position here. His projects are supported by the Russian Science Foundation.
At the request of the readers of the newspaper "Search", the head of the Center for Cell Technologies of the INC, Acting director of the Institute, Doctor of Biological Sciences Natalia Mikhailova, told about the work of St. Petersburg cytologists.
– We really had something to report to our colleagues. The Institute of Cytology was actually the first in the country to study stem cells and apply fundamental knowledge in practical medicine. Our employees, for example, have developed an effective cellular product – the dermal equivalent – for the treatment of patients who have received severe burns and suffer from non-healing trophic ulcers. The product, consisting of a collagen matrix and living human skin cells, is applied to wounds, and they heal quickly. Cells (dermal fibroblasts) they secrete substances, stimulate the work of the patient's own cells, and collagen is the main structural protein of the skin. I note that traditional methods of treatment are not yet able to cope with trophic ulcers.
The Ministry of Health supported us, and the country's clinics were able to use our cellular product from 2006 to 2011. More than 500 patients received effective treatment, and the lives of burn patients were saved. However, it was impossible to continue working with a well–proven product - it had to be re-registered, but we could not do this. At that time, there were no rules in the country allowing the use of human cells. A paradoxical situation: biologists created new methods of treatment with the help of stem cells, but they were not allowed to try them out in practice. Because of this, without exaggeration, tragic inconsistency, the development of cellular technologies has stalled, and we have begun to lag behind the West. This went on for about five years, until Federal Law No. 180 "On the Circulation of Biomedical Cell Products" came into force at the end of 2016. The congress held in Moscow was the first meeting of scientists-developers and, importantly, doctors who will now be able to apply technology. An outstanding event for our field of science! The credit for this belongs to Academician V. Tkachuk, who took the initiative to hold the forum.
With the adoption of the law, the situation has radically changed, and biological institutes have become more active. But the question of financing stem cell-based developments immediately arose. It is simply impossible to carry out such expensive work for small grants (for example, RFBR). Our institute was extremely lucky in this situation – we already had a grant from the Russian Science Foundation. At the end of 2014, we won a prestigious competition for the implementation of a comprehensive program for the development of the INC "Molecular and cellular technologies for the treatment of socially significant diseases". The Foundation was almost the first to finance these fundamental research and support the development of promising methods of using stem cells for the treatment of serious diseases, the creation of new technologies, equipping laboratories with modern technology, training personnel for the emerging field of regenerative medicine and bringing it to the world level.
– Did you have many competitors?
– Yes, 12 academic institutes and leading universities. But only three biological institutes were among the winners. We received a grant for five years in December 2014 and started working on the project at the beginning of the next one. A lot has been done during this time: we have expanded the research of stem cells and methods of their production to create effective cellular products. We develop them together with doctors for the replacement of organs and tissues (restoration of the bladder, damaged bone tissue), including in patients with tuberculosis. We are developing fundamental studies of induced pluripotent stem cells for modeling almost any human tissue. In this area, the Institute occupies a leading position thanks to the work of corresponding member of the Russian Academy of Sciences A.Tomilina.
Our pride is the Center of Cellular Technologies, built taking into account the requirements for clean rooms and the international GMP standard. This was one of the central tasks of the grant. We opened the center in May 2017 (in the top picture), the first among biological institutes and, I think, very quickly – in 2.5 years.
Photographs provided by N.Mikhailova
The center occupies only 100 sq. m., but, as they say, the spool is small and expensive: it meets the highest cleanliness requirements. This means that we give a guarantee and there can be no contamination during cell cultivation. This year our clean production has managed to confirm its high class. Now we are preparing equipment and technologies for accreditation. This is being done for the first time, and while we are waiting for the final regulations from Roszdravnadzor and the Ministry of Health of the Russian Federation.
The center is equipped with the most modern equipment that allows you to obtain high-quality cell cultures, including for high-performance screening, to increase the standard cell mass for the production of cellular products.
For example, we have one of the first automated cell culture systems in Russia – CompacT – of the Sartorius company worth more than 100 million rubles. There are two such installations in the country, but only ours works in clean rooms. The cells, let me remind you, are cultivated manually, this process is extremely time-consuming, taking a lot of time. And the robotic installation, according to the specified protocols, does this without human participation around the clock, without being distracted by lunch and smoke breaks, and most importantly, unmistakably. Thanks to the proven advanced technology, as well as standard methods and materials, we can conduct preclinical studies of the drugs being created. The moment is fundamental: now we are ready to test new drugs ourselves, to conduct experimental tests not on animals, but on cell models, observing how cells react to the novelty. That is why it is so important to develop and improve such technologies.
Modern equipment allows us to "build" standard cellular products, which after certification can be transferred to clinics. First of all, this is a product that has already received permission for the treatment of severe burns and ulcers, which I mentioned. It can also be recommended for disaster medicine. When a lot of people were injured in Perm during a fire at the Lame Horse Club, they were taken to St. Petersburg clinics, and there was a huge demand for our cellular product. Then we threw all our efforts into its production. It's a shame when disasters happen, they call us: "Urgently give your product!", and when the danger has passed, they require a certificate of certification. Now we have to register our developments according to the new rules defined by Law No. 180. And although the method has proven itself perfectly (it has been used in clinics for five years), all stages, including preclinical and clinical studies, will have to be repeated again. But there is hope that the Ministry of Health will meet us halfway and simplify the registration procedure. This will be the first biomedical cellular product that we are going to register. Currently, tests are being conducted of such a remedy for restoring the bladder, which, as I said, is in demand by tuberculosis patients. Another technology is designed for bone replacement (implantation of prostheses for bone replacement, including restoration of tuberculous bone tissue). We conduct promising research with ophthalmologists: we develop products for the restoration of eye tissue defects using stem limbal cells.
– At what level are your technologies? Is there a backlog?
– Of course, there are analogues of our cellular products abroad, especially concerning the treatment of burns. And yet I will name the important advantages of our developments: they are not inferior to Western ones in terms of efficiency and are much cheaper. What we are lagging behind, I repeat, is in the pace of implementation: at first, the application was hindered by the absence of the law, now, I'm afraid, it will take five years until our methods are certified. In the meantime, the country is still forced to buy expensive medicines and technologies abroad.
– Has the Institute managed to solve the issue of personnel training, as required by the grant?
– We have been working intensively in this direction and have made significant changes in recent years. More than a hundred specialists participate in the project supported by the Russian Academy of Sciences, more than half of them are young people, including graduate students and students (for an institute with about 240 researchers, it seems quite good). The main thing is that young scientists work with enthusiasm, their eyes are burning, they are interested in us. Many write articles and are published in leading, highly rated foreign publications. And yet there are not enough specialists, first of all, capable of cultivating cells and servicing robotic equipment. Therefore, we are discussing the development of educational programs with St. Petersburg and Polytechnic Universities to train highly qualified specialists combining knowledge of cellular, molecular biology, materials science with skills to work on the latest equipment.
– The grant ends in 2018, what will happen next with the center and the scientific direction?
– Of course, we will continue to develop this important area of regenerative medicine. And already now, continuing to implement the RNF project, we are looking for funding. I would like to note that the scientific reputation of the institute, extensive experience and achievements (the opening of the center, articles in foreign journals, research and development) significantly facilitate this difficult task and attract the attention of pharmaceutical companies, medical organizations, universities to us. During the three years of the grant, the INC has concluded about 20 contracts, including agreements for consultations and training of employees of Russian organizations of various departments. There are also agreements with foreign universities, for example, with Munich (joint research on the use of nanoparticles and mesenchymal stem cells used in oncology). An agreement was recently signed with the Center for Systems Biomedicine of the University of Luxembourg – we will create biocompatible matrices for the cultivation of neurons. Together with our American colleagues (Tafts University, Boston), we are engaged in testing biocompatible titanium materials for bone prosthetics. There were sponsors supporting us in the implementation of this project, including our founder FANO of Russia, foreign and domestic companies. Knowing about our scientific capabilities and excellent equipment, the institute began to involve in testing new drugs. One contract for preclinical research has already been executed according to the GLP standard. This year, an agreement was signed on the creation of a consortium together with colleagues and medical organizations from Kazakhstan – they are interested in methods of treating burns, trophic ulcers and intend to acquire our technology, jointly create new cellular products. We will participate with Belarus in the implementation of the Union State program. And all these developments have taken place over the past three or four years.
– Let's go back to the congress held at MSU: how were your employees' reports received?
– I think it's very good. Our reports on promising stem cells and the use of biomedical cell products aroused great interest among the participants. For example, the report of Academician N. Nikolsky was devoted to endometrial stem cells and the possibility of their use for the treatment of infertility in women. A huge amount of work has been done, in particular, the effectiveness and safety of these cells have been proven. M.Khotin presented a new infrastructure (according to the international GMP standard) for the creation of biomedical cell products that can be transferred to clinics, in accordance with the requirements of the law FZ-180. The interest in our work can also be explained by the fact that classical methods of treatment are still powerless against severe diseases, so the use of biomedical cell products has reached a high level. For example, the Research Institute of Oncology in St. Petersburg makes antitumor vaccines based on bone marrow cells and tumor cells of the patient (biotherapy), which have shown a significant antitumor effect. This technology also had permission from the Ministry of Health for use, but now it must be registered again – how many patients will not receive treatment on time! Our country ranks almost first in the world in terms of the number of amputations of limbs – due to the fact that chronic trophic ulcers are not yet treatable. And suddenly there are methods of wound healing, and patients recover without surgery, returning to a full life. Such technologies should receive support from the state and the Ministry of Health: the use of new methods reduces the disability of the population and mortality. This is how the growing and replacement of tissues and organs with stem cells, which seemed fantastic, become a reality. The significance and importance of these revolutionary methods, in my opinion, are so great that I would compare them to space flights.
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