Medicine and Mathematics

"Man and Medicine" – 2010. Part 1. Medicine and Mathematics – achievements and prospects
F. Snegirev, "Weekly Pharmacy", 26.04.2010.

On April 12-16, 2010, the XVII Russian National Congress "Man and Medicine" was held in Moscow on the basis of the Russian Academy of Public Administration under the President of the Russian Federation. The congress was co-organized by the Ministry of Health and Social Development of the Russian Federation, the Ministry of Education and Science of the Russian Federation, the Russian Academy of Sciences (RAS), the Russian Academy of Medical Sciences (RAMS), the Russian Medical Academy of Postgraduate Education, Lomonosov Moscow State University (where the Faculty of Fundamental Medicine has been functioning for more than two decades), the Foundation "Health".

Welcoming the forum participants, Alexander Chuchalin, President of the Congress, Academician of the Russian Academy of Medical Sciences, Professor, Director of the Federal State Institution "Scientific Research Institute of Pulmonology of the FMBA of Russia", stressed the importance and practical benefits of this regular event: For more than 20 years, Russian scientists have been coming together in order to understand the trends that are taking shape in medical science and practical healthcare in the last period of time. Starting his introductory report devoted to the review of the main achievements of medical science in 2009, the chairman recalled the interpretation of the verb "to prove" given in the explanatory dictionary of V.I. Dahl: "To convince of the truth of what with arguments, evidence; to confirm what is indisputable" – and noted that for these purposes modern medical science actively operates in the language of mathematics.

– When we talk about medicines, we are trying to understand the truth of a person and his life – and evaluate this truth with the help of tools and approaches of exact sciences and high-precision technologies used in medicine: therefore, these tools and approaches are defining the life of the person himself. The main principle formulated in the Hippocratic oath remains unchanged for us: primum non nocere, the main thing is not to harm. Therefore, no matter how great medications are, we must always weigh all the pros and cons of their effectiveness and safety – both in themselves and in terms of use in various categories of patients (gender, age, presence of concomitant pathology, taking other medications, genotypic and other features) and with different types of pathology.

What will determine the search and creation of new medicines? The search for biological markers (BM) is now considered as a real way to create a new generation of medicines – and scientific progress in this area, which is possible to achieve by 2025, is completely based on the concept of BM. Alas, this concept is often blurred (which is typical, including for Russian science) and signs and symptoms that cannot meet the criteria of BM are brought under this definition. It should be understood that BM is proteins circulating in human blood in abnormally high concentrations. BM is produced by a plasma cell, which, for various reasons, has a broken biological program, as a result of which it begins to diligently synthesize a protein, which ultimately leads to the launch and emergence of certain pathological processes and mechanisms.

The BM concept makes it possible to identify the most important mechanisms of the course of the disease, at the same time, BM are targets for the creation of new active pharmaceutical ingredients (API). It was the discovery of BM that led to the creation of substitution therapy, genotyping, and ultimately taught the correct choice of a clinical strategy for managing patients with a variety of types of pathology. Today, especially for the Western world, the problem of a sharp increase in degenerative diseases of the nervous system is acute – and from the standpoint of BM, the search for appropriate medicines that could control the processes of their pathogenesis is actively underway. The area of great clinical intrigue is anti–inflammatory drugs - very serious developments have taken place in this area in the following directions:

• search for new targets in the treatment of autoimmune diseases,
• personalization of treatment,
• creation of treatment programs that modify the course of the disease.

BM research is particularly active in the field of oncology (as dreamed of by academician N.N. Blokhin, who was one of the first in the world to create a specialized institute dealing with the problems of molecular oncology), in particular in the context of:

• earlier diagnosis of malignant neoplasms,
• development of a new generation of antitumor drugs,
• personalization of treatment programs.

Along with BM, the appearance of modern medicine determines the rapid development of monoclonal antibodies (MA), which are increasingly used in clinical practice. In the coming years and decades, this trend will strengthen: according to the forecast given by the speaker, by 2024, the MA market will exceed 30% of the total market of medicines. Factors inhibiting vascular endothelial growth are of great clinical interest. If in some clinical situations it is necessary to increase the vascular endothelium (which is acceptable, for example, in diabetic foot, in patients with coronary heart disease, etc.), then in the case of cancer it is necessary to use drugs, in this case MA, restraining the growth of vascular endothelium: thus, avastin has proven itself well in extensive clinical practice (for the treatment of breast cancer, colorectal cancer, lung cancer, ovarian cancer). Cetuximab is used for epidermal growth factor receptors in colorectal cancer, head and neck cancer, lung cancer (in the treatment of which particularly noticeable progress has been made recently). The course of a number of serious diseases (non–Hodgkin's lymphoma, congenital autoimmune hemolytic anemia, rheumatoid arthritis, etc.) suppresses MA with a pronounced antineoplastic effect - rituximab. However, alas, new diseases always arise with new medications: neurologists were among the first to describe severe side effects in the form of encephalopathies when using MA. At the same time, the use of these medicines requires special training of a doctor. Here – as in transplantology – it is impossible to make mistakes anywhere. And if the doctor does not have the appropriate qualifications, if he is not allowed to see the patient with all his individual characteristics and difficulties, if he cannot assess the interactivity of medicines, it is better: do no harm.

The new theory of medicine, which is now being vigorously discussed, is based on the personalization of treatment – the creation and implementation of treatment programs that modify the course of the disease. When approaching the treatment of patients, the doctor should choose the right drug and individualize it as much as possible. Today, patients or their relatives often reproach doctors: "Do not treat us according to standards!" – this is an extremely important ethical aspect, which should be reflected in the professional codes of doctors. In general, with the discovery of the human genome, there is a boom in clinical medicine: new diseases are constantly being described. Modern fundamental research irrefutably shows that a new pathology really exists – we simply do not see approaches to it. It is very important to see a new human pathology: today this task is acute for scientists all over the world – and many opportunities have already been accumulated for its implementation, including Russian scientists. Among the most promising technologies used by them, the speaker named:

• the proteome/genome program,
• mass spectrometry,
• advances in cellular and molecular biology,
• pharmacogenomics,
• bioengineering,
• math.

It is no coincidence that the assembly lecture at the opening of the congress was delivered from the mouth of a mathematician: Viktor Sadovnichy, Academician of the Russian Academy of Sciences, Professor, Rector of Lomonosov Moscow State University, President of the Russian Union of Rectors, a mathematician-computer scientist who has a personal relationship to solving many medical problems, and the head of the university, in which, in fact, the development of medicine and medical education in Russia began (actively continuing to this day). Created in 1755 at the suggestion of M.V. Lomonosov, the Imperial Moscow University – the first Russian higher educational institution – became not just the first center of medical education in the country, but also the cradle of domestic medicine as a whole (it is symbolic that it was opened in the building of the main pharmacy, on Red Square, where the Historical Museum is now located). The principles of teaching at the Faculty of Medicine were laid down by the great founder of the University M.V. Lomonosov, who recommended that, for example, when teaching anatomy, the professor must "show the structure of the human body in practice at the anatomical theater and teach students in their medical practice." Many graduates and professors of Lomonosov Moscow State University played a key role in the development of medicine, made up its golden fund: M.Ya. Mudrov, A.A. Ostroumov, G.A. Zakharin, I.M. Sechenov, S.P. Botkin, N.I. Pirogov, N.V. Sklifosofsky, N.F. Filatov, S.S. Korsakov, V.P. Serbsky, F.F. Erisman, V.F. Snegirev, G.N. Gabrichevsky, N.N. Burdenko and many others. The greatest genius of Russian medicine (note from the editorial board: not only Russian, but also Ukrainian – and world), a graduate of Moscow State University N.I. Pirogov: the scale of his services to medicine – as a scientist, surgeon, organizer of medical activity – is truly unique. He made discoveries that literally changed the face of medicine and determined new ways of its development; his proposed method of "ice" anatomy and layer–by-layer dissection put anatomy on a solid scientific foundation - this kind of tomography of the nineteenth century was a revolutionary discovery; anatomical atlases created by him reproduce the relative positions of organs and tissues with an accuracy comparable to that obtained on modern high-tech scientific equipment. Pirogov actually laid all the foundations of military field medicine: for the first time he applied ether anesthesia and performed about 10 thousand such operations, invented plaster bandages, introduced the selection of wounded according to severity, on his initiative, sisters of mercy appeared at the front. The famous graduate of the Medical faculty of Moscow University, N.V. Sklifosofsky, became the dean to whom the university owes its clinical campus: thanks to his authority, he managed to get a plot of land on Devichy Field and build university clinic buildings there – at the end of the XIX century. at the XII International Congress of Physicians in Moscow, this clinical complex of Moscow University (and this is 13 clinics and 6 specialized institutes) was recognized as the best clinic in Europe.

The speaker extensively covered the history of the development of the Moscow medical school: from such great graduates of Moscow University as N.I. Pirogov and A.P. Chekhov, to the separation of the medical faculty from its composition with the transformation (1930) into the First Moscow Medical Institute (which in 1958 joined the Moscow Pharmaceutical Institute as a faculty), since 1990 – Moscow Medical Academy named after I.M. Sechenov, – and up to the present day, when with the help of a supercomputer of Moscow State University (which occupies the 12th place in the world among its own kind in terms of operating capacity), scientists of the Faculty of Fundamental Medicine reach the submolecular level and find out the most subtle mechanisms of the course of diseases in the development of new drugs and therapeutic and diagnostic methods. The report testified to the current high level of development of Russian fundamental medical science – and this level is impressive. Thus, a new principle of drug design has been developed at the Research Institute of Physico-Chemical Biology of Moscow State University: targeted intracellular delivery of biologically active substances. It was possible to synthesize a new mitochondrial antioxidant, which is a prototype of drugs designed to combat a number of diseases in elderly patients (scientists have achieved outstanding results – it remains to introduce them into clinical practice, which requires significant financial investments). The joint work of doctors and scientists of the Pulmonology Research Institute with employees of the chemical and Mechanical-mathematical faculties of Moscow State University has led to the development of new methods of non–invasive diagnostics of respiratory diseases: based on the analysis of exhaled air condensate, they allow determining the content of a number of disease indicator substances in it (for example, biosensers have been created that can diagnose the content of hydrogen peroxide in exhaled in the air).

But what are mathematicians doing in these collaborative studies? It turns out that condensate is characterized by a significant number of parameters, and this abstract multiparametric space can be divided into "zones" of bronchial asthma, chronic obstructive pulmonary disease and a healthy state – thereby a strictly mathematically justified state of these lung conditions is given (along with determination in laboratory conditions). However, the importance of mathematics for medicine is not limited to the strict formalization of experimental data. There are many other examples of the use of mathematical modeling by MSU scientists for medical purposes. Prototypes of vestibular prostheses for patients with vestibular function disorders are being developed: the key link is mathematical modeling of vestibular biosensors (these works are a continuation of research on dynamic simulation of the effects on the human body of all stages of aerospace flight). A medical instrument equipped with a sensory system simulating the tactile function of a human finger has been created. On the basis of advanced mathematical methods of image processing and pattern recognition, an experimental batch of medical devices designed for the study of removed tissues and work inside cavities (in the thoracic and abdominal cavities, retroperitoneal space, joint cavities) was created, the technology of their mass production and clinical application was developed, their medical tests are conducted in leading clinics and specialists give them the highest rating. Such equipment (which has no world analogues) could be created only by the combined interdisciplinary efforts of scientists-mathematicians, doctors, specialists of industrial and defense enterprises.

The results of numerous scientific studies that are used in medicine, and the very logic of the development of university education naturally led to the need to resolve the issue of the place of medicine at Lomonosov Moscow State University – that is, the revival of the tradition of university medical education, moreover, the restoration of historical justice. And such a decision was made in 1992, when the academic council of the university supported the rector's initiative to create a faculty of fundamental medicine – so, medical education was recreated at a new level of science development at Moscow State University and medicine returned to its walls de jure (although it never left them de facto). Modern medical education is impossible without a powerful own clinical base – this idea was put forward immediately when creating the Faculty of Fundamental Medicine. And today, with the unconditional support of the Moscow government, the construction of the MSU medical center has already been completed: this year it is being put into operation in full – 11 buildings of the center with a total area of 45 thousand m2 have been erected on 6 hectares of the new university territory, where clinics, operating rooms, laboratories equipped with the most modern medical equipment are located. This makes it possible to carry out not only complex diagnostics, but also to develop priority areas of modern biomedicine and biotechnology; provides for the widespread introduction of modern hospital-substituting technologies. During the classes, students have the opportunity to directly observe the performance of surgical operations and complex diagnostic methods. Thus, the MSU Medical Center is a unique, modern, multidisciplinary university clinic: a clinic of the XXI century that meets international standards of medical education and healthcare. In front of the entrance to the medical center, it was decided to erect a monument to A.P. Chekhov. His diploma of graduation from the medical faculty of Moscow University and the title of a zemstvo doctor was signed by Dean N.V. Sklifosofsky in 1884. A.P. Chekhov not only glorified Russian literature, but also remained a doctor all his life: he was distinguished by a special, sincere and caring attitude towards patients, he treated many of them for free (as if in defiance to his literary fame, in a joking way he himself set his priorities, saying that medicine is his lawful wife, and literature is his mistress). The future monument to the great humanist will become a symbol of the fact that Lomonosov Moscow State University is the cradle of outstanding citizens of their homeland, the place that allows the talents of scientists, doctors, writers to be fully revealed," the rector stressed.

The Faculty of Fundamental Medicine of Moscow State University has all the necessary conditions for the training of highly qualified specialists, a feature of the training of medical students is their fundamental scientific education. In the first years of their studies, they take serious university courses in mathematics, physics, chemistry, biology, which are taught by the best professors of the mechanical-mathematical, physical, chemical, biological faculties. This allows graduates to easily master modern ideas and methods, the latest medical technologies in their future work, which means they can be in demand in all medical institutions of the country. Scientists of the faculty have achieved a number of important results, for example:

• cell therapy and tissue engineering technologies are being developed: for this purpose, methods of isolation and purification of stem cells are being created, on the basis of which tissue equivalents are being constructed that can restore the structure and function of damaged organs and tissues. In animal experiments, stem cells and tissue engineering structures obtained using biocompatible (or biodegraded) matrices are transplanted - these structures restore the skin after burns, replace bone and cartilage defects;
• therapeutic genes have been created that cause the growth of blood vessels, which makes it possible to improve blood supply to tissues without surgical intervention and stop degenerative processes in organs. These gene-therapeutic methods can be used to treat myocardial infarction, stroke, limb ischemia, trophic disorders, the consequences of injuries and wounds, joint diseases, etc. (the tests were successful, the results are at the stage of implementation into clinical practice);
• based on the analysis of human genotypic and phenotypic polymorphism, new methods for identifying people's predisposition to various diseases are proposed. For this purpose, large DNA collections and corresponding databases are being created, algorithms for multifactorial analysis of premorbid traits are being developed in order to search for predictor genes or combinations of them that have predictive value for predicting the development and course of diseases or their complications (all this activity is based on the joint work of physicians, mathematicians, computer scientists, representatives of a number of other disciplines and scientific branches);
• especially for the medical center, scientists from the Faculty of Fundamental Medicine, together with scientists from the Faculty of Physics, the Institute of Nuclear Physics and the Institute of Mechanics of Moscow State University, are developing a device for radiation therapy of oncological diseases – the so-called new generation cyberknife. It is based on a unique linear accelerator with connecting electron energy, which has no analogues in the world (all operating installations of this type have constant electron energy, and this device allows you to irradiate tumors and metastases with a thin beam of high-energy electrons in one session in more than a thousand directions simultaneously).

The most important area of application of mathematics in general – and the efforts of scientists of the Faculty of Fundamental Medicine in particular – is the creation of new medicines. In modern conditions, this task is only possible for developed countries – countries with a high level of development of fundamental science and a powerful high-tech information infrastructure. According to V. Sadovnichy, today one of the main issues for Russia is the production of modern domestic medicines. Not the purchase of outdated products from biopharmaceutical factories, where the fermenter is the most outstanding device, but the creation of the latest high–tech medicines of Russian production. Today, MSU has a base for this, which opens up significant opportunities, including in the creation of medicines: first of all, a super–booster is needed for this - there are 7 such in Russia, 3 of them work at MSU. In general, it was previously believed that Russia is not a player in the field of high computer technology and has fallen behind forever, but over the past two years there has been a breakthrough in this field. Firstly, the Russian Federation took the 7th place in the world, and the Lomonosov Moscow State University supercomputer, which has a capacity of about 500 trillion operations per second, took the 12th place (second only to 9 supercomputers of US defense centers and one each from Germany and China): in a situation where this was considered impossible, this is a great success.

Lomonosov is successfully used at the initial stages of drug development, consisting in the search for new chemical compounds – inhibitors that block pathological areas of active protein centers. So, together with the hematology center of the Russian Academy of Medical Sciences, work is underway to create a new remedy for thrombosis and search for a new generation of blood substitutes. In just a year and a half (instead of 7-10 years when using traditional approaches), new thrombin inhibitors were discovered, significantly surpassing foreign analogues in their activity; preclinical trials have been completed and preparations are underway for clinical trials of the created new antithrombotic agent. The commissioning 2 years ago of another lower–power supercomputer – Chebyshev (peak performance of 60 teraflops) - reduces the duration of the search for inhibitors to several months. With its help, the development of HIV integrase inhibitors (as the basis for a new drug for AIDS), as well as compounds capable of stopping the division of cancer cells by suppressing a number of the main pathophysiological mechanisms of this process, were carried out. Meanwhile, Lomonosov, commissioned in 2009, reduces the search for inhibitors to several days: due to this, the range of new drug development has significantly expanded. Currently, calculations are being carried out on the Lomonosov supercomputer for new projects, among which is the development of urokinase inhibitors (blocking of which slows down the growth of tumors and metastases). The main tool in the initial stages of development is an original doping program: the search for appropriate molecules in the active center of the target protein, taking into account the energy of the inhibitor –protein bond (the greater the energy of this bond, the more effective the inhibitor and the better the drug developed on its basis). Now the search is underway for these new molecular groups that effectively bind to the active center of urokinase; a unique research experiment on doping of more than 3 million molecules has been launched. The candidate inhibitor molecules found as a result of this doping will be further experimentally investigated already at the Faculty of Fundamental Medicine. Thus, in fact, the process of stable development of the latest drugs is launched. At this hypersensitive first stage – when selection is carried out from millions and tens of millions of molecules, which in order to assess their binding to the active center of the protein requires billions and tens of billions of operations (which is possible only for a super booster) – the foundation is laid for all further stages of drug creation: pharmaceutical development, clinical trials, registration studies, up to before entering the market: for this, pharmaceutical companies must already pick up these fundamental developments.

The Rector spoke in favor of preserving the best traditions of Russian education and science, for such an education system in which all the available scientific and pedagogical potential will be fully used, which will make young people truly fundamentally educated and capable of creation. The fundamental nature of education is the key to the successful development of science, medicine, the economy, and the country as a whole. At the same time, a negative assessment was given to attempts to exclude fundamental knowledge from university education or to belittle their role in the learning process. But without them, it is impossible to understand the nature of phenomena, and therefore it is impossible to train specialists who will not be thoughtless performers, but creative workers, people capable of carrying out evolutionary development in the relevant fields of activity. It is equally important that a person who has received a deep fundamental education is able to comprehensively and systematically assess all the consequences of certain management decisions and provide conditions for the sustainable development of society. In addition, fundamental education is the basis for further education and retraining of a person throughout his life. The speaker unequivocally condemned the approach when science is viewed through the prism of short-term economic feasibility, rapid financial returns. The transfer of market mechanisms to the sphere of education and science is fraught with irreparable strategic losses, which in the future may be more tangible than today's benefits. After all, the results of fundamental research, after implementation and with the beginning of practical application, as a rule, many times exceed the results of applied work – both in terms of final economic efficiency and social significance.

Recently, as part of the interdisciplinary scientific and educational complex of Lomonosov Moscow State University, for the first time in Russia, the Institute of Man was created, which unites the efforts of specialists engaged in the study of man by various methods of natural science fundamental research, integrates a variety of fields of science - biology, physics, chemistry, mathematics, anthropology, and various other humanities. The scientific activity of the Human Institute is one of the priorities of the University's development program, developed until 2020. in accordance with the "Law of the Russian Federation on Lomonosov Moscow State University" adopted at the end of the year and the decree of the President of the Russian Federation. The creation of such an institute as part of the Moscow State University was the dictate of the time. The speaker recalled that according to N.D. Kondratiev's theory, development obeys the law of long waves (or cycles) when one economic structure is replaced by another. The current, 5th way (associated with the achievements of electronics, computer technology, the use of laser, telecommunication technologies, etc.) in our years is changing to the 6th, which, according to most experts, will be determined by the convergence of nano-, bio–, information and cognitive technologies. And these are the branches of knowledge where the main actor should be a person. Therefore, all outstanding scientific achievements should be in the name of man," Academician V. Sadovnichy summed up.

The next publication of the cycle is devoted to the experience, state of affairs and prospects of development in the field of drug provision in the Russian Federation.

Portal "Eternal youth" http://vechnayamolodost.ru29.04.2010