Medical Genetics - V. M. Zaporozhan 2005

Introduction to Medical Genetics
Subject and Tasks of Medical Genetics. History of Medical Genetics
Main Milestones in the History of Medical Genetics

Throughout human history, facts regarding the existence of heredity and Variability in various organisms, including humans, have been accumulated and analyzed. Pre-scientific concepts of inherited differences among people already existed in antiquity, appearing in the works of Hippocrates, Aristotle, Democritus, and other ancient Greek philosophers. Even in the writings of Hippocrates, The Role of heredity in THE ORIGIN OF diseases was noted. In the 18th and 19th centuries, works emerged addressing The Significance of heredity in the onset of polydactyly (Maupertuis, 1752) and hemophilia (Nasse, 1820). Many hereditary conditions, such as Down syndrome, neurofibromatosis, and congenital Connective Tissue Dysplasia, were described as nosological entities. However, only with the birth of genetics as a science did it become possible to truly understand the Etiology and subsequent Pathogenesis of hereditary pathology.

The fundamental classical laws of inheritance were discovered by G. Mendel, who in 1865 published the results of his research in the paper "Experiments on Plant Hybrids". At the same time, the foundations of Human Genetics were laid. Its founder is considered to be the English scientist F. Galton, who in 1865 published two short articles titled "Hereditary Talent and Character". F. Galton was the first to apply biometric Methods to The Study of human Quantitative Traits, developed the principles of genealogical, twin, and dermatoglyphic methods, and established the theoretical framework of eugenics. Eugenics is a scientific field focused on improving the hereditary constitution of humans through the preferential reproduction of individuals possessing desirable traits (positive eugenics) and preventing the reproduction of those with severe illnesses (negative eugenics).

G. Mendel's work remained unknown to the majority of biologists for 35 years because his research was far ahead of the general scientific development of his time, and his contemporaries failed to appreciate its significance. The official birth year of genetics is considered to be 1900, when the laws of inheritance were independently rediscovered by three scientists: H. de Vries (the Netherlands), E. Tschermak (Austria), and C. Correns (Germany).

The history of the Selection/4.html">Development of Genetics since 1900 can be divided into four overlapping stages without rigid boundaries.

The First stage is the era of classical genetics (from 1900 to 1930). During this period, Mendelism was firmly established, The phenomenon of linked inheritance was discovered, and the Gene theory and chromosome theory of heredity were formulated. Developments in the doctrines of phenotype, genotype, and gene interaction were also of vital importance.

The Second Stage (from 1930 to 1953) is known as the neoclassical period. In these years, induced mutagenesis and the possibility of artificial mutagenesis were discovered; the principles of Population Genetics and evolutionary genetics were substantiated; it was definitively proven that the gene is a discrete unit of heredity; the Central dogma of genetics concerning the role of genes in metabolic processes ("one gene — one enzyme") was formulated; and evidence was obtained regarding the genetic role of DNA as the carrier of Genetic information.

The Third Stage (from 1953 to the early 1970s) marked the rise of Molecular Genetics, the starting point of which is considered to be the publication of The Structure of DNA by J. Watson and F. Crick in 1953. At this stage, the fundamental MOLECULAR MECHANISMS OF the expression of hereditary information were discovered—METABOLISM/28.html">The Genetic Code, the main Stages of Protein Synthesis, DNA Replication, and Operon gene regulation in prokaryotes.

The Fourth Stage is The Emergence of "mobile" genetics, characterized by the advancement of Introduction/32.html">Genetic Engineering and The Development of DNA analysis techniques. Its beginning can be marked by the discovery of restriction Enzymes (W. Arber, H. Smith, and D. Nathans) and Reverse Transcriptase (H. Temin and D. Baltimore) in 1970, as well as the creation of the first recombinant DNA in 1972 (S. Cohen, H. Boyer). This made it possible to study the subtle molecular Nature of the gene and the mechanisms regulating gene activity, manipulate individual genes, and transfer genes from some organisms into the Cells of others, thereby creating biological systems that never existed in nature. A major milestone of genetics at the turn of the 21st century was the decoding of the genomes of numerous organisms, including humans. Molecular and genetic engineering approaches provided a new level of research in developing the Theories of the gene and mutagenesis, biochemical and evolutionary genetics, immunogenetics, human genetics, medical genetics, and other Branches of the science of heredity and variability.

The development of medical genetics was closely intertwined with the achievements of classical genetics. The key Milestones in the History of Genetics that are significant for the development of human and medical genetics are presented in Appendix 1.

One of the pioneering works in medical genetics that applied Mendel's Laws to explain The Nature of a disease was authored by the English physician A. Garrod, titled "The Incidence of Alkaptonuria: A Study in Chemical Individuality" (1902). The author concluded that alkaptonuria could serve as a model for inborn errors of metabolism and is inherited in a Mendelian recessive manner. He is regarded as the founder of human biochemical genetics. In 1908, A. Garrod grouped four hereditary conditions (alkaptonuria, albinism, pentosuria, and cystinuria) under the common designation of "inborn errors of metabolism".

In 1934, A. Følling identified phenylketonuria as an independent nosological entity.

In 1940, K. Landsteiner and A. Wiener discovered the Rhesus factor, proving that hemolytic disease of the newborn results from maternal-fetal immunological incompatibility. In the 1960s, it became possible to prevent hemolytic disease of the newborn by administering anti-Rh Antibodies to mothers at risk of developing this condition.

During this same period, Monogenic Disorders and the Molecular Basis of human heredity were actively investigated. In 1948, Gibson first demonstrated that methemoglobinemia (an autosomal recessive disorder) is caused by impaired activity of the enzyme NADH-dependent methemoglobin reductase, while in 1952, the Coris discovered glucose-6-phosphatase deficiency in Gierke's disease (a form of Glycogen storage disease). In 1949, L. Pauling and colleagues established that Sickle-Cell Anemia is caused by an abnormality in Hemoglobin structure. This discovery spurred similar research, and in 1956, V. Ingram determined that sickle-cell anemia results from the substitution of glutamic acid by valine at the sixth position in the ß-globin chain. The discovery of abnormal Hemoglobins allowed for a detailed Study of the consequences of Mutations. It was revealed that mutations can lead to Amino Acid Substitutions, frameshifts, or the premature Termination of the polypeptide chain. It was demonstrated that many inborn errors of metabolism are caused by mutations altering the structure of enzyme Proteins. In 1953, Jervis demonstrated the absence of phenylalanine hydroxylase in phenylketonuria, and H. Bickel reported the efficacy of a low-phenylalanine diet for this condition. From that time onward, pathogenetic Treatment for Metabolic Disorders became achievable. In 1961, R. Guthrie developed a Mass Newborn Screening method for phenylketonuria. In the early 1960s, glucose-6-phosphate dehydrogenase deficiency in drug-induced hemolytic anemia and the enzymatic defect in galactosemia were described. Biochemical research techniques were continually refined, paving the way for the Prenatal Diagnosis of enzymopathies.

A turning point in the history of medical cytogenetics occurred in 1956, when two Swedish scientists, J. Tjio and A. Levan, established that the normal human diploid chromosome Complement consists of 46 Chromosomes. Medical genetics, which had not been considered a clinical discipline prior to 1956, acquired a clear subject of study: the Cell Nucleus. In 1959, French cytogeneticist J. Lejeune proved that Down syndrome is caused by the presence of an extra chromosome 21 in the karyotype. In the early 1960s, chromosomal numerical abnormalities associated with Turner syndrome and Klinefelter syndrome were discovered, and Patau, Edwards, and cri-du-chat syndromes were described, along with various translocations, deletions, duplications, polyploidies, and other chromosomal and genomic mutations. This enabled the diagnosis of Chromosomal Disorders, facilitated by the refinement of cytogenetic techniques. Since 1966, Prenatal Diagnosis of Chromosomal Abnormalities has been performed via amniocentesis.

Thus, by the early 1960s, medical genetics had evolved into a clinical discipline. The Major Groups of Hereditary diseases had been identified, diagnostic methods and prenatal fetal testing had emerged, and preventive treatments for certain enzymopathies had been developed.

The subsequent advancement of medical genetics as a science was driven by the development of molecular-genetic Research Methods, the study of gene structure, and the refinement of prenatal diagnostic techniques. Significant insights into The Human Genome and those of other organisms were yielded by the international Human Genome Project. The project officially commenced on October 1, 1990, with J. Watson as its first director, followed by F. Collins in 1993. The project's goals included: determining The nucleotide sequence of the human genome; constructing a high-resolution genetic map; sequencing and mapping the genomes of other model organisms vital for biological research (such as *Escherichia coli*, Yeast, *Drosophila*, and the mouse); developing advanced DNA research technologies; and addressing the ethical, legal, and social implications of human genome research. Originally planned for 15 years, the project was successfully completed ahead of schedule, with a draft sequence of the human genome published in February 2001 and the final version in April 2003. A vital role in identifying susceptibility genes for multifactorial disorders was played by the project's ancillary program investigating human genetic polymorphism.

Building upon the breakthroughs of molecular biology, genetics, and genetic engineering, a new branch of medical science—molecular medicine—emerged. Its scientific foundation rests on the identification of thousands of structural and regulatory genes, the elucidation of the genetic basis and molecular mechanisms underlying many monogenic and Multifactorial Diseases, the recognition of genetic factors in the ETIOLOGY AND PATHOGENESIS of various pathological states, and the proof of each individual's genetic uniqueness. The core hallmarks of molecular medicine are its personalized approach and preventative focus.

The most significant milestones in contemporary molecular medicine include the following (V. S. Baranov, 2004):

— the development of precise, efficient, and universal Diagnostic Methods for Hereditary Diseases at any stage of ontogenesis, including prenatally;

— the establishment of approaches for precise personal identification (genomic fingerprinting) and the genotyping of Organs and Tissues designated for transplantation;

— the ESTABLISHMENT OF THE experimental and clinical foundations of Gene Therapy for both hereditary and non-hereditary diseases;

— the initiation of research in Pharmacogenetics, pharmacogenomics, and genetic Epidemiology based on data concerning individual biochemical (genomic) profiles;

— the active Development of the molecular foundations of preventive medicine.

The Development of Medical Genetics in the USSR and Ukraine

In the USSR, medical genetics developed successfully during the 1920s and 1930s. The pioneer of clinical genetics in the Soviet Union is considered to be the eminent neuropathologist S. M. Davidenkov (1880–1961). He organized the world's first medical-genetic consultation clinic (1929) and published several books on the genetics of Hereditary diseases of The Nervous system.

From 1930 to 1937, the development of medical genetics was pursued at the Medical-Biological Institute, which was renamed the Medical-Genetics Institute in 1935 under the directorship of S. G. Levit. The institute conducted research in cytogenetics, twin studies, as well as clinical and Formal genetics. In 1937, the institute was closed, and S. G. Levit was repressed. For a long period—from the early 1940s to the early 1960s—genetics research in the USSR was banned, and many prominent geneticists faced political repression.

The development of medical genetics in the USSR resumed in the early 1960s. Active participants in the revival of Soviet genetics included V. D. Timakov, S. M. Davidenkov, V. P. Efroimson, O. O. Prokofieva-Belgovskaya, E. F. Davidenkova, S. A. Neifakh, and E. E. Pogosyants. These breakthroughs in medical genetics spurred the establishment of a dedicated medical-genetic service network across the USSR during the 1970s and 1980s. A substantial contribution to the development of genetics in Ukraine was made by S. M. Gershenzon (1906–1998), who discovered the mutagenic properties of Nucleic Acids and Viruses, and demonstrated the feasibility of reverse Transcription. In Ukraine, medical genetics began to be integrated into the operations of specialized research institutes in Kyiv (such as the Institute of Molecular Biology and Genetics of the National Academy of Sciences of Ukraine, and the Research Institute of Pediatrics, Obstetrics, and Gynecology of the Ministry of Health of Ukraine). Furthermore, the first specialized research institute was established in Lviv, and the first Republican Medical-Genetic Center was founded in Kryvyi Rih. In 1988, the specialty of medical geneticist was officially added to the nomenclature of medical positions, and following an order by the Ministry of Health of Ukraine, a network of medical-genetic facilities was established nationwide. In 1989, the first Department of Medical Genetics was founded at the Kyiv Medical Academy of Postgraduate Education by Professor T. I. Buzhiyevska, alongside the establishment of another Department of Medical Genetics at Kharkiv State Medical University.

Today in Ukraine, medical-genetic care is provided to the population through a network of Medical-Genetic Counseling clinics, offices, and centers, while highly specialized care is delivered by dedicated research institutes under the Ministry of Health and the National Academy of Medical Sciences of Ukraine. In 2003, the Ministry of Health of Ukraine, in cooperation with the Academy of Medical Sciences, issued an order entitled "On Improving Medical-Genetic Care in Ukraine" aimed at reforming the STRUCTURE OF THE medical-genetic service, actively implementing modern diagnostic, therapeutic, and preventive technologies, and applying the latest scientific advances in medical genetics and molecular biology to improve public health. The primary areas of focus for Ukrainian medical geneticists include establishing a State Genetic monitoring System, refining prenatal screening methods, introducing advanced approaches for the Prevention and Treatment of Hereditary disorders and congenital birth defects, and conducting research in multifactorial pathology, pharmacogenetics, oncogenetics, and population genetics.

Medical students at universities study medical genetics as a distinct academic discipline.