FROM MOLECULES OF DISEASE ON TO HEALTH MOLECULES

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by Acad. Mikhail PALTSEV (Russian Academy of Sciences and Russian Academy of Medical Sciences), rector of the I. M. Sechenov Moscow Medical Academy (MMA); Alexei IVANOV, Dr. Sc. (Medicine), Vsevolod KISELEV, Dr. Sc. (Biol.) - both deputy directors of the Institute of Molecular Medicine of the MMA

In September 2000 the I. M. Sechenov Moscow Medical Academy-with so many research and academic departments, clinics and laboratories under its wing-set up yet another body, the Institute of Molecular Medicine, where biochemists and gene engineers, pharmaceutists and biotechnologists pooled efforts in basic and applied research, in particular, toward developing a new generation

During these past five years the young research collective, concentrating on priority objectives, has scored certain results. But before going into its activities, let us survey in brief outline major development trends in modern medicine.

For centuries medical doctors have been relying by and large on their practical experience and intuition, and they have been diagnosing cases by just questioning their patients. A cohort of the best Russian medics of the 19th century performed miracles in their masterly diagnostics. But the tables were turned in the 20th century with the introduction of high-precision techniques (X-rays, ECG, etc.), when hard proof came to play an essential role in diagnosing a particular pathology from factual clinical evidence. The public health system, too, imposed rigid diagnostic standards, especially in the

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Western countries where medical insurance gained broad ground due to financial expenses and risks involved.

The progress of 20th-century medicine became possible thanks to achievements of basic research into man's vital activity and its problems. Whereas the previous body of knowledge did not go beyond evaluation of empirical experience, the focus now was on the results of basic research as materialized in diagnostic, therapeutic and preventive methods. Bedside observations were relegated to secondary importance. Clinical surgery and highly effective therapy of many heretofore incurable diseases became a practical reality owing to techniques not known before, e.g. modes of controlling the functions of the organism, the finest metabolic and enzymatic processes as well as the passage of hereditary information. Truly revolutionary changes have been wrought of late. In scope and significance they are comparable to breakthrough discoveries in biology in the mid-20th century, which touched off the turbulent development of molecular biology and biochemistry, biophysics, physiology, genetics and pathology.*

Decoding of the human genome is one of the epic events whose remote consequences even geneticists are unable to predict so far. Needless to say, it will take a good deal of time to identify the functions of all genes (which are DNA structural and functional sites) and learn how they interact with one another and with the environment. But even at this stage it is clear that information obtained in solving this thorny problem will attain immense significance in health protection. Understandably, this will raise ethical issues bearing on


* See: S. Popov, "Medicine of Tomorrow Born Today", Science in Russia, No. 3, 2005. - Ed.

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the very nature of man* that we have never encountered in our clinical practice; and we shall have to stop and think how much and how far we are prepared to go in using and modifying the human genome.

The record of achievements includes the conceptualization of apoptosis, or the pre-programmed death of cells. The medical and scientific community the world over is showing an unflagging interest in this field of research, for an understanding of the molecular mechanisms implicated in cell death-be it under normal or pathological conditions-helps to learn the cause of a disease and more, to realize a targeted treatment strategy.

Cultivation of stem and precursor tissue cells**, now practiced in experimental biology, is certainly a notable achievement, too. In all likelihood clinical and prophylactic medicine of the 21st century will be predicated on cell biology techniques.

Molecular medicine is involved with decoding the mechanisms whereby pathological information is realized. Defects in the gene structure or in protein synthesis lead to a variety of diseases with aberrations specific to each of them. Works carried out in these past few years have made gene expression regulation a real thing, and this enables us to act on a pathological process. Proceeding from the available body of knowledge, we are searching for molecular markers of socially significant diseases (oncological, cardiovascular, infectious) so as to diagnose them at the earliest stage. We should also realize that the symptoms of one and the same disease may differ depending on the individual features of man's metabolism. For instance, millions of people contract influenza during seasonal outbreaks, but the course of this infection is quite different for different people.

Molecular medicine makes it possible to design treatment programs relative to each particular case, which is quite in keeping with the approach of Russia's forward-thinking doctors of the 19th century: treat the patient, not the disease! Hence the conclusion: knowing the mechanisms of different pathologies we can develop and optimize curative methods for dysfunctions of the cell and of the organism as a whole. A proper choice of medication and modes of its delivery to the sickly cell can be a good strategy for treating cases at the molecular-cellular level.

In the last fifteen years humankind has amassed a huge body of information which allows us to approach the vital activity of man and other biological objects as molecular interaction. This is yet another factor opening up truly unlimited opportunities for new type pharmaceutics.

It is quite logical that the Research Institute of Molecular Medicine was established within the Moscow Medical Academy-a venerable institution with nearly a 250-year record behind it (its "forefather", so to speak, was the Department of Medicine of H. M. Moscow University founded in 1758, and its "next-of-kin" predecessor-the First Moscow Institute, or College, reorganized into an academy in 1990). The Moscow Medical Academy has always been a happy blend of education and research. It is not accidental that the first president of the USSR Academy of Medical Sciences (set up in 1944, i.e. during the Second World War) was the famous military surgeon Acad. Nikolai Burdenko, with the pathoanatomist Acad. Alexei Abrikosov elected vice-president-both were departmental heads at the First Moscow Medical Institute. This laudable tradition is still alive-the heads of the leading research centers of the Russian Academy of Medical Sciences double as heads of MMA departments.

Today the Research Institute of Molecular Medicine has three departments (those of cellular and molecular pathology, assimilation of new medications, research-and-development) as well as four laboratories (molecular biology and biochemistry, human molecular genetics, biotechnology, gene engineering). Research scientists of all these subdivisions join hands in common problem solving, though each of them has a narrow line of specialization. Thus, the Department of Cellular and Molecular Pathology is studying the role of stromaepithelium interaction in controlling cell lesions, reparation, differentiation and growth, which are the basic processes taking place in the organism both under normal and under pathological conditions. Primary attention here is attached to dysfunctions concomitant to malignancies, namely to the possible role of the stroma (connective tissue) in inducing carcinogenesis. Its range of interests likewise includes the specifics of the inflammatory-reparative process in wound healing as well as distinctive features of stable and unstable (vulnerable) atherosclerotic plaques (patches), and their formative causes.

The Laboratory of Molecular Biology and Biochemistry focuses on the molecular-cellular mechanisms of carcinogenesis (tumor growth). Gene and protein engineering helps develop preparations of targeted action


* See: R. Petrov, "Bioethics", Science in Russia, No. 3, 2001. - Ed.

** See: V. Yarygin et al., "These Totipotent, Omnipotent Cells", Science in Russia, No. 1, 2004. - Ed.

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and their selective transportation into a malignant cell with the use of specific protein vectors (carrier molecules responsible for the high-efficiency transport of initiators into the target cell). This laboratory has synthesized medical drugs against cancer (including FLUSTAT for prostatic cancer and SINTAZIN for mammary gland cancer, both patented in the Russian Federation).

The mechanisms of carcinogenesis is also a priority research area for the Laboratory of Human Molecular Genetics. In collaboration with the P. A. Hertzen Moscow Oncological Institute it has developed a set of diagnostic and therapeutic markers. The former (diagnostic markers) are especially good in the early detection of cervical carcinoma, prostatic and lung cancer, for they allow to spot cell genome disorders well before morphological changes of the cell. This actually noninvasive diagnostics holds out good prospects for risk factors in particular. As to the therapeutic markers, attending doctors have a special stake, for they can assess the efficiency of the chosen therapy, forecast the further course of a malignancy and detect micrometastases (secondary cancers), if any.

It has been proved already: many widespread diseases (such as cardiovascular, oncological, endocrine, immune system maladies) are not by one single gene, but rather by a set of genes in which polymorphic DNA variants may enhance the risk of a pathology and predetermine the further course of a disease. A system of genetic markers may be developed for such DNA variants relative to a concrete pathology to make it possible to define risk groups and realize effective monitoring during annual prophylactic medical examinations. The Laboratory of Molecular Genetics has obtained such markers for mammary and prostatic cancer risk groups.

The research staff of this laboratory is looking into the causes of female and male infertility (sterility). In this connection we should mention pre-implantation diagnostics for married couples wishing to have a baby but compelled to resort to extracorporal fertilization ("test-tube babies"). Just one cell of a blastomere (a fertilized ovum at the earliest stages of cell division) would suffice to see the presence or absence of chromosomal defects in the thus extracted DNA. These cells can be dispatched by rapid mail delivery to our laboratory from any city, and the results will be ready in eight hours. Such diagnostic methods are practiced in other countries, too. However, experts of the Institute of Molecular Medicine have managed to cut down costs tenfold through a multiprimer polymerase chain reaction. (A defect of a particular chromosomal site, or locus, is detected by means of what we call a primer, a synthesized fragment of DNA. The polymerase chain reaction provides for polymerase-mediated replication of DNA and RNA for spotting gene mutations; polymerase is an enzyme implicated in this procedure.) That is to say, we can make as many as ten analyses in one test-tube alone!

The Institute of Molecular Medicine (MMA) is paying much attention to the early detection of oncogenesis and to respective medication with the use of different preparations to check tumor growth-especially effective for hyperplasias, or the earliest stages of malignant tumors. Thus, one of the projects of the Laboratory of Biotechnology is related to diseases associated with the human papilloma virus. Its staff is carrying out fundamental research into identification of the main molecular targets of such oncoviruses. A series of monoclonal antibodies* has thus been obtained capable of "recognizing" the main viral oncoprotein E7 responsible for papilloma neoplasms. Accordingly, a special diagnosticum (diagnostic procedure) is elaborated toward early detection of the malignant degeneration of epithelial cells of the neck of the womb (cervical tumor), for it is at the earliest stage of cervical cancer that remedial action is most effective. World practice, by the way, has no test system like that. Yet another technique developed jointly with the Russian Research Center of Roentgenoradiology allows to detect mammary gland hyperplasia as a precursor of malignancy. The whole process is amenable to monitoring and, if need be, to quick remedial intervention. The diagnostic procedure involves no extra health hazards.

The Laboratory of Biotechnology has developed a set of chemical compounds offering good promise as anti-tumor drugs-they control cell division which, as we know, goes out of control in tumors. Two such compounds have already been registered and are undergoing clinical tests. One, INDINOL (our joint product with the domestic Mirax-Farma Co.) acts upon cell proliferation (division) in female reproductive organs. It has a good remedial effect for mastopathies, papilloviral infections, particularly, for respiratory papillomatosis of


* Monoclonal antibodies-specific antibodies obtained from hybrid cells formed via fusion of normal lymphocytes of immunized animals with malignant cells. A monoclonal antibody inherits from a lymphocyte an ability to synthesize a definite antibody, while from a malignant cell it gets an ability of open-ended proliferation. Monoclonal antibodies are a good diagnostic remedy. - Ed.

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the larynx. The other preparation, EPIGALAT, which is a potent inhibitor of angiogenesis, might be used for rectal and mammary cancers, and gastric ulcer. Although it has completed a round of lab tests, we need another few years before bringing it to the pharmaceutical market.

Designing gene-engineering products for tumor therapy is yet another trend in our work. One such vaccine for cervical carcinoma has shown a high-performance effect under laboratory conditions, and it has been patented already.

The tuberculosis problem is likewise getting close attention at the Institute's Laboratory of Biotechnology. The ТВ incidence rate has been up of late in Russia, since the mycobacterium M. tuberculosis readily acquires resistance to drugs currently in use. Consequently, we should look for therapeutic approaches other than chemotherapy and conventional medicines. One is a new vaccine for ТВ immunotherapy; it will be effective if the infection has been caused by polyresistant bacterial strains where chemotherapy is useless. Besides, the new vaccine is free of shortcomings of the tuberculous BCG vaccine, still being used for mass vaccinations of the population. As to the new ТВ vaccine, its future depends on wide-scale laboratory and clinical tests.

But yet another product of ours has already been handed to pharmaceutical companies. It involves a new Mantoux reaction-a test for early detection of ТВ. The Mantoux test developed a hundred years ago is highly nonspecific and often gives wrongly positive results by diagnosing ТВ in healthy individuals. Why? Because the Mantoux reaction (test) was evolved at the time when one had but a vague idea of the structure of microorganisms, including ТВ pathogenic bacteria. Relying on present-day data, our experts have created a gene-engineering product that guarantees 100 percent ТВ differentiation from a post-vaccinal response to BCG. This preparation will be produced strictly in keeping with international pharmaceutical standards (Good Manufacturing Practices), which implies export possibilities.

The Gene Engineering Laboratory is designing bio-chips for medical diagnostics.* Jointly with the RAS Institute of Theoretical and Experimental Biology (Pushchino, Moscow Region) it has launched full-scale biotechnological production of biochips, biochemical accessories to them and chip-detectors with original software.

Two departments-one concerned with practical use of new medical drugs, and the other-with research and development-are important branches of our Institute. No rapid entry of innovative medicines and diagnostic techniques into the market is possible without their involvement.

Contemporary knowledge is inconceivable without collaboration of many research collectives. That is why our Institute is working in close touch with the Russian Academy of Sciences and the Russian Academy of Medical Sciences in the field of molecular medicine. Pooling efforts with RAS Institute of Gene Biology and the RAS Institute of Development Biology (named after N. K. Koltsov), we have begun joint research into embryonal stem cells. The bank of stem cells, now being set by the Institute of Molecular Medicine on the instructions of the RF Ministry for Public Health and Social Development, will give a new dimension to this work. A nonprofit form of cooperation within the framework of the Center of New Medical Technologies (TEMP project) and involving more than twenty different research centers has shown its high efficiency. R&D updates are carried in the journal Molekulyarnaya meditsina (Molecular Medicine) brought out by the Sechenov Moscow Medical Academy and Meditsina (Medicine) Publishers. Broad international conferences on biosecurity and molecular medicine, now conducted for the second year in succession at our Institute under the aegis of the Sechenov Medical Academy, likewise further consolidate of the scientific community.

...The advent of the molecular medicine age is a significant landmark on the long path of man's cognition of his own self and of the world around him. Its progress is intimately allied with the further headway of the natural and technical sciences. Their onward march is precipitous indeed. Diagnostic and treatment remedies, still within laboratory walls, will become a state-of-the-art practice tomorrow. This is what we are doing at our Institute of Molecular Medicine-speed up their assimilation in clinical practice.


* See: A. Mirzabekov, "Biological Microchips", Science in Russia, No. 2, 2003. - Ed.


Опубликовано 01 октября 2018 года




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