By Vladislav BARANOV, Corresponding Member of the Russian Academy of Medical Sciences, D. O. Ott Institute of Obstetrics and Gynecology, St. Petersburg
Science has moved into the 21st century under the sign of biology and genetics. At long last biologists have been able to decipher the human genome and read in full (sequence) the "thread of life", a giant molecule of DNA encoding not only the past of the human race (phylogenesis) and not only the record of each and every individual (ontogenesis). The DNA structure also carries the molecular scenario of the future evolution of man...
Like any other major scientific discovery, the human genome sequencing has given rise to new important trends in research*, also in molecular medicine that diagnoses, treats and prevents hereditary and nonhereditary diseases with the use of genes, or, rather, nucleic acids.
Now, in what way is molecular medicine different from conventional medicine well known to us since childhood? First and foremost, in the universality of diagnostics based on precise methods of genetic analysis. Its focus is on prevention: molecular medicine can reliably predict the incidence of this or that disease. In this sense it is a predictive medicine. It caters to every single individual in terms of medication (selecting remedies for each and every patient, the way a tailor fixes your suit to order). Molecular medicine makes a wide use of gene therapy, that is it uses genes and gene products for treating different hereditary and non-hereditary diseases.
As a matter of fact, human individuals differ not only in social characteristics (birth, upbringing, education and the like) - they
* See: Yu. Altukhov, "Ecogenetics", K. Sudakov, K. Anokhin, "Genes, Brain, Behavior", Science in Russia, No. 3, 2002. - Ed.
"Gene network" of bronchial asthma.
also differ in the molecular structure of their heredity. As shown by comparative studies, molecular structure variability in the genome of different individuals amounts to 0.1 percent. That is differences (caused by substitution of separate "letters") occur quite often, in every 400 characters (signs), which means as many as 9,000,000 substitutions per genome. Such variants are rather frequent within genes too, something that may result in polymorphism when proteins are synthesized with much changed characteristics as compared with normal proteins. Such functionally different proteins (isozymes), hormones and the like account for an individual's biochemical pattern, his biochemical "fingerprint", as we say.
Intragenic substitutions are not always neutral. Such genes-rather, the products of their activity-perform less efficiently and make one vulnerable to a particular disease. In the words of Dr. Francis Collins, who is in charge of the international Human Genome Project, none of us is perfect after all. With the ever more genetic tests becoming available, he says, we may discover some kind of mutation in our organism predisposing us to a disease.
Indeed, it is with the help of genetic tests that a predisposition to particular diseases can be detected in man of any age, embryos including. But only definite genes, what we call disease predisposition genes (morbidity genes) are subject to such analysis. Although posing no immediate threat to one's health, these genes may be activated under certain unfavorable conditions (external effectors like air and water pollution, drugs, dietary habits, and so forth) and cause a variety of diseases, such as diabetes, osteoporosis, atherosclerosis, myocardial infarction and other rather frequent maladies. Predisposition genes may trigger psychic disorders, malignant diseases and what is known as multifactori-al illnesses. Most of the above diseases occur due to mutations of many different genes (gene networks) responsible for definite metabolic processes. All this is the domain of predictive medicine which is concerned with spotting mutation-related dysfunctions.
Pharmacogenetics is an important part of predictive medicine. It zeros in on individual responses of the organism to pharmacological preparations (as many as 100,000 people the world over are reported dead every year from wrong do-
Humankind's "genetization" in the 21st century.
sages of drugs when individual responses are neglected).
A batch of genetic tests is now widely used in laboratories and diagnostic centers so as to detect carriers of mutant genes touching off mucoviscidosis (congestion of the enhanced viscosity secrete in a particular organ), metabolic disorders, hemophilia (hereditary disease that prevents the blood from clotting normally, so that a small injury may result in excessive bleeding) and other grave hereditary diseases. This is particularly important to high-risk families having a sick child already. Genetic tests make it possible to identify carriers of mutant genes and, through timely prenatal diagnostics, preclude the birth of another sick baby. However, certain neu- rodegenerative and oncological diseases (say, breast and colon cancer) make themselves manifest rather late, in adults of mature age. This is where early diagnostics methods will be appropriate.
Gaining ever wider currency are tests aimed at detecting a hereditary predisposition to diabetes, osteoporosis, atherosclerosis, cardiovascular diseases as well as neuropsychic and oncological maladies. The world literature lists something like 150 to 200 genetic tests available for clinical practice. And they are in wide use in the United States and Western Europe, especially in France, Great Britain and Federal Germany.
France, for one, is applying the SESAM system. It incorporates the computer interpretation of genetic tests data as well as data of biochemical, serologic and immunological tests. This system involves as many as 80 tests and more, with the data processed by a special computer program, PPMA, which includes expert evaluation proper, tutorials for practioners, medical consulting, and reference data for the population at large. It was France that became the venue of the First International Congress on Predictive Medicine in 2001. As to the PPMA computer program, it centers on data evaluation of various genetic tests, in the first place, on studying the status of genes within the detoxication system, which are responsible for man's sensitivity to external effects, in particular, to chemical drugs, other medicines and xenobiotics.
Britain, in turn, is realizing a full-scale Biobank project to collect genetic information on more than 500 thousand Britons of different races and ethnic groups with the aim of studying diabetes, cancer,
Basic phases of the detoxication process.
Alzheimer's disease and cardiovascular diseases. If realized, this project will usher in a new era in medicine, for it will enable medics to prognose and treat diseases with an eye to patients' individual genetic peculiarities.
We in Russia have no programs like that yet. However, predictive genetic tests are underway in molecular laboratories and centers of Moscow, St. Petersburg, Novosibirsk, Tomsk and Ufa.
Way back in 1995 we at the D.O. Ott Institute of Obstetrics and Gynecology (Russian Academy of Medical Sciences) began research in predictive medicine. We concentrated on the predisposition to endometriosis, a common multifactorial disease when particles of the endometrium (mucous membrane) of the body of the womb are carried into various tissues and organs. This malady that often results in sterility affects 10 to 55 percent of the women.
As we have found in a series of experiments, endometriosis occurs mostly in women who have zero allele* variants of genes responsible for the 2nd phase of detoxication of xenobiotics, namely of glutathione transferase MI and TI (GSTMI 0/0 GSTTI 0/0) in combination with the sluggish form of M acetyl transferase (NAT-2). What is more, a mismatch in such alleles in female patients afflicted with endometriosis stimulates their resistance to medication, especially if it involves the use of immunomodulators. The testing of detoxication system genes allows to identify women with a hereditary predisposition to this grave disease, prognosticate its further course and select an optimal strategy of treatment.
We have obtained reliable results on a correlation of unfavorable detoxication genes (GSTMI, GSTTI) for such common pulmonary diseases as bronchial asthma and grave chronic bronchitis. And should there be several zero allele variants (GSTMI 0/0, GSTTI 0/0) in the genome, the probability of bronchial asthma in an infant increases tenfold and more! Zero alleles (GSTMI 0/0, GSTTI 0/0) compounded by the sluggish form of placental* glutathione transferase (GSNPi) occur three times as often in women prone to premature deliveries, something that unfortunately holds for 10 to 25 percent of the female sex. Detoxication system genes are found to be implicated in such widespread diseases as lung cancer and alcoholic cirrhosis of the liver. Enzymes controlled by these genes are important for metabolism of all xenobiotics, including various pharmacological preparations.
Yet detoxication system genes are but one of the many gene complexes, the object of predictive medicine. Other genes, too, are of
* Alleles -different forms of one and the same gene within identical sites (loci) of homologous chromosome pairs. -Ed.
* Placental -related to placenta, the organ in many female animals through which the unborn young, or fetus, receives food and oxygen and gives off waste.
essential significance for hereditary predisposition. For instance, those controlling the transmembrane transport of metabolites, and genes whose products are all-important to cell processes.
Our research scientists have found that the presence of alleles of the collagen* gene CoIIAI and the gene of the vitamin D-VDR-3 receptor increases individual sensitivity to a heavy form of osteoporosis 17.8 and 5.4 fold, respectively. The prognosis is still worse if functionally weakened alleles of these two genes are present in the organism. And their presence in the gene of androgen receptors ADR may mean a predisposition to prostate cancer. The allele form in combination with extended deletion (loss) in the gene of lymphocyte receptors CCR-5 means enhanced sensitivity to HIV.
It's a sad fact: people are born with a set of genes capable of triggering some grave disease. Such kind of hereditary predisposition is strictly individual. A testing of corresponding genes allows to detect high-risk cases and optimize the treatment strategy of multifactorial diseases.
The testing of several different genes at once, not one or two, can give us fairly objective information on a hereditary predisposition to any diseases that "trail" from parent to kid. Prognostication techniques have been developed for over 25 multifactorial diseases, such as myocardial ischemia, sugar diabetes (diabetes mellitus), hypertension, breast cancer, prostate and lung cancer, drug addiction, bronchial asthma, alcoholism, psycho-neurological disorders...
Other research centers in Russia, apart from our Institute, are also working on hereditary predisposition to disease. In St. Petersburg, there are the N.N. Petrov Oncological Research Institute (involved with all sorts of tumors); I.P. Pavlov Medical University (concerned with cardiovascular diseases, atherosclerosis); Research Institute of Experimental Medicine of the Russian Academy of Sciences (atherosclerosis); and Gerontology Institute (drug addiction, cardiovascular diseases). Working in this field in Moscow are the Research Institute of Genetics and Selection of Industrial Microorganisms (diabetes), and the Research Center of Medical Genetics, Russian Academy of Medical Sciences (oncology, diabetes, atherosclerosis, cardiovascular diseases). In Ufa, this is the Ufa Scientific Center of the Russian Academy of Sciences (drug addiction, diabetes, atherosclerosis, heart ischemia); and in Tomsk, this is the Medical Genetics Research Institute operating under the auspices of the Siberian Branch of the Russian Academy of Medical Sciences (cardiovascular diseases, hypertension, bronchial asthma, and so on).
We might as well add that identification of human genes already known to us and discovery of new polymorphisms expand sizably the possibilities of genetic testing both in finding hereditary predisposition and in medical-and-genetic consulting. Up- to-date technologies can be of much assistance here. For instance, the use of microchips making it possible to test thousands of genetic polymorphisms in one or in several patients simultaneously. This is particularly important for obtaining a picture of the genetic structure of a country's population and for planning an effective system of prevention with respect to common multifactorial diseases. We are pleased to say that the V. A. Engelgard Institute of Molecular Biology in Moscow (Russian Academy of Sciences) has pioneered in the microchip technology of gene polymorphism.
Thus thanks to genetic tests we can get rather objective data on diseases we "take", and do it already in the initial phases of embryonal growth. In other words, we can learn as early as that what kind of mutant genes we carry. We can learn what characteristics of our genome may pose a real threat to the health of our kith and kin, and lead to grave, incurable diseases in ourselves too. The use of prenatal diagnostics of hereditary diseases in clinical practice, the screening of mutant gene carriers, and genetic testing-all that can be very helpful toward developing databases for individuals and families alike. If supplemented with data on the caryotype (a set of chromosomes) and the genetic number (an individual genetic code determined by genomic fingerprinting), such databases might evolve into something like a genetic identity card of sorts.
The advantage of such "identity" might be obvious: we ought to be in the know about the weak and strong points of our hereditary makeup (genome). And doctors-our family doctor in particular-will foresee and even prevent many untoward consequences for our health or for the health of our near and dear ones.
And yet all too many people hate to know all about the "reefs" of their heredity. And then such kind of information should be strictly confidential, this is a must. These and many other problems must be resolved toward harmonic adaptation of predictive medicine to practice.
* Collagen -an essential protein of the connective tissue of man and animals. - Ed.
Illustrations supplied by the author.
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