The role of genetics in modern medicine

Relevance
In 2020, genetics as a science turned 120 years old. This event was marked by the acquisition of new knowledge and the discovery of breakthrough technologies in the field of natural sciences and humanities. Many public health problems, including those associated with hereditary diseases (monogenic, chromosomal, multifactorial, epigenetic and tandem repeat expansions), as well as congenital malformations, environmental and social diseases, owe their more complete scientific understanding precisely to genetics. This allows the development of new diagnostic, therapeutic and preventive technologies and approaches in modern medical science and practice.
The structure of genetics in medicine
Human genetics studies the phenomena of human heredity and variability at all levels of its organization and existence: molecular, cellular, organismal, etc. [1].
Medical genetics studies the role of heredity in human pathology, patterns of transmission from generation to generation of hereditary diseases, develops methods for diagnosing, treating and preventing hereditary pathologies, including diseases with a hereditary predisposition [1,2].
Medical genetics includes general genetics (studies the universal manifestations of heredity and variability in all living organisms, including humans), clinical genetics (studies the etiology, pathogenesis, clinic, diagnosis, treatment and prevention of human hereditary diseases) and laboratory genetics (studies laboratory methods diagnosis of human hereditary diseases) [1, 2].
Within the framework of medical genetics, the following are developing: genomics (studies the genome as a set of genes of an organism), cytogenetics (studies the patterns of heredity in relation to the structure and functions of organelles, especially chromosomes), molecular and biochemical genetics (studies changes in DNA and RNA at the molecular level), immunogenetics (studies the hereditary factors of immunity), developmental genetics (studies the process of implementing genetic information during the individual development of organisms), population genetics (studies the distribution of allele frequencies and their change under the influence of the driving forces of evolution: mutagenesis, natural selection, gene drift and gene flow) , pharmacogenetics (studies the hereditary basis of the variability of the effects of drugs and allows you to predict the effectiveness and safety of using drugs in patients), environmental genetics (studies the genetic aspects of the interaction of the organism under the influence of the environment), nutrigenetics ( studies genetic predispositions to diseases, taking into account genetic variations and nutrient intake), toxicogenetics (studies the processes of absorption, distribution and elimination of toxins), etc. [1, 2, 3].

Possibilities of modern genetics in medicine
Genetics is the science of the foundations of life, the laws of its development, heredity and variability, information codes that form the basis of all living things [2]. Despite the active development of genetics, today it is a young science, it is only 120 years old. Officially, the birth of modern genetics is considered to be 1900, the year of the rediscovery of Mendel's laws [1]. Although the foundations of genetics were laid long before that, genetics received official status only after independent publications by G. de Vries, K. Correns and E. Cermak outlining the basic laws of inheritance. At the dawn of its birth, genetics was considered as the science of heredity and variability, and only after the discovery of the fundamental laws of molecular biology did the essence and place of genetics in the development of biological and medical sciences become clear [4, 5]. The development of information technologies that operate with digital codes, which make it possible to describe and program any processes using mathematical symbols, made it possible to compare genetics and computer science and realize all the limitless possibilities of genetics [6].
Medicine has always been looking for an explanation of pathophysiological processes in the body, and only thanks to genetics has it become possible to explain in more detail the processes of growth, development, functioning, health problems, aging and death of the body [1, 2]. Today, about 5,000 well-described hereditary diseases are known. Genetic databases such as OMIM (Online Mendelian Inheritance in Man) [2] contain descriptions of more than 37 thousand different hereditary anomalies [1, 2, 3]. And these clinical descriptions are replenished every day.
Today it is already known that among all the reasons for hospitalization of patients, 20-40% are hereditary diseases [7]. In countries with a developed healthcare system, genetic disorders determine: 80% of mental retardation [2], 70% of congenital blindness [2], 50% of congenital deafness [2], 40-50% of spontaneous abortions [2] and miscarriages and 20-30% infant mortality [2]. About 30% of perinatal and neonatal mortality is due to congenital malformations and hereditary diseases with other manifestations [1]. Every year, 5-5.5% of children are born with hereditary diseases or congenital malformations [3], part of the hereditary pathology manifests or is diagnosed later (up to advanced age), or if it is present, it is not diagnosed at all [3]. Almost all severe clinical cases, unexplained pathophysiological reactions, diseases with a progressive course and ineffective classical therapy can be safely called syndromes of hereditary diseases, or pathology with hereditary burden [1]. And all this variety of pathology can be explained from the point of view of genetics. In this regard, genetics can be called a fundamental clinical discipline with enormous possibilities and prospects for therapy.
Some authors [1, 2, 3] highlight the main features of modern genetics, such as the accuracy of generalizations and their fundamental nature, the objectivization of the understanding of pathophysiological processes and modern research methods, both on the organismal and molecular, cellular, tissue, organ, population-species and biospheric levels [2].
With the beginning of the international project The Human Genome Project, HGP (Human Genome Project), the foundation was laid for the development of the fundamental foundations of personalized medicine, the development of new medicines and methods of treatment [2, 8]. The project remains the largest international project ever undertaken in biology and medicine [3, 8]. It began in 1990, under the direction of James Watson. In 2000, a working draft of the genome structure was formed; by 2003, 85% of the human genome had been sequenced. The project was completed in 2022, when the complete sequencing of the human genome was achieved [2]. The bulk of sequencing was performed at twenty universities and research centers in the USA, Great Britain, Japan, France, Germany, and China [1, 8].
Genome sequencing has made it possible to reach a qualitatively new level in the development of medicine, namely personalized medicine.
Personalized medicine is a new organizational model for building medical care for patients, which is based on the selection of individual therapeutic, diagnostic and preventive agents that are optimally suited for the biochemical, physiological and genetic characteristics of the body [9]. Its main goal is to personalize and optimize treatment and prevention in order to eliminate negative consequences and complications that appear due to individual genetic characteristics. Personalized medicine uses innovative diagnostic methods and targeted drugs (drugs that target the pathological focus without harming healthy cells of the body) [9].

The term "personalized medicine" was first used as the title of Keval Jain's monograph in 1998 and began to be mentioned in MEDLINE in 1999, however, most authors associate "personalized medicine" with pharmacogenomics and pharmacogenetics [10]. "Personalized medicine" based on the genetic characteristics of the organism has synonyms: targeted, matched, genotype-based, individualized or based on an individual approach; information-based, systemic, genomic (genomic medicine), predictive (predictive medicine) or customized medicine (tailored medicine), drugs with a genetic action (pharmacogenomics, pharmacogenetics, pharmacoproteomics), integrated healthcare (combining diagnostics, screening, prevention, treatment and monitoring) [9,10].
A significant contribution to the development of personalized medicine is the creation of a genetic passport. The technique allows not only to determine hereditary diseases, but also the predisposition to the development of certain multifactorial and oncological diseases [8,10]. When creating a genetic passport, it is possible to predict the age of development of diseases and plan preventive measures. A genetic passport allows you to determine the national origin and ethnic composition of genes (gene drift), predisposition to certain sports, abilities for science and art, personal qualities, response to drugs, habits, assimilation of vitamins and microelements, as well as food addictions and metabolic characteristics [eleven]. All this information allows you to make the life of the individual better and more conscious.
The development of genetics has made it possible to bring care to cancer patients to a new level. Oncogenetics is developing in several directions: prenosological and early diagnostics, pharmacogenetics in oncology, and outcome prediction [12]. By identifying oncogenes, it is possible to develop both preventive measures and, at the early stages of tumor development, to diagnose them, without wasting time on analyzing the development of clinical manifestations of the disease, and to prescribe targeted treatment [12]. At present, it is difficult to overestimate the role of genetics in understanding the mechanisms of the onset of tumors, diagnosis and treatment of oncological diseases. The profile of molecular genetic changes underlies the updated classification of human neoplasms, the identification of their germline mutation is the main stage in the laboratory diagnosis of hereditary oncological syndromes, the nomenclature and scope of tests for the detection of somatic mutations are expanding every year to select personalized targeted therapy in oncology, the increasing importance the participation of a geneticist in counseling patients is gaining [12]. It must always be remembered that any malignant neoplasm is a genetic disease.

Individual intolerance to drugs has long been known, but with the advent of genetics, this phenomenon has become possible to explain. Pharmacogenetics combined genetics and pharmacology [13]. For the first time, an association between an individual's individual response to a drug and a genetic defect in the enzyme was established for the muscle relaxant succinylcholine. Later, similar studies were carried out for the drugs primaquine and isoniazid. Pharmacogenetics has been especially rapidly developed after the introduction of the drug warfarin (Wiskonsin Alumni Research Foundation), which has shown high efficiency in preventing thromboembolic complications in patients with myocardial infarction, to the market. At the same time, the frequency of hemorrhagic complications while taking the drug reached 10-16%, but an attempt to remove it from clinical practice led to a significant increase in post-infarction complications [13].
Today, the polymorphic nature of many enzymes involved in the metabolism of drugs and transporters responsible for their penetration and excretion from cells has been established. Determination of enzyme activity using genetic typing is one of the simplest and most effective pharmacogenetic approaches for drug dose adjustment and pharmacotherapy optimization [14]. The activity of drug-metabolizing enzymes often varies widely in healthy individuals. As a result, the drug elimination rate can differ by 40 times [13,14].
Identification of individual metabolic characteristics plays an important role in intolerance to certain foods (for example, milk) and in the appointment of certain drugs (oral contraceptives and hormone replacement therapy) [15]. Determination of the genetic cause of individual sensitivity to the drug allows you to adjust the dose, increase the effectiveness of therapy and avoid complications.
Gene therapy is a method of treating hereditary pathology based on the introduction of healthy genes into the patient's body [16]. Gene therapy is closely related to genome editing. In turn, genome editing is a new genetic engineering method used in gene therapy and in research on functional genomics. The method is based on the use of specific nucleases capable of inducing site-specific changes in the genome. Insertion, deletion or movement of DNA fragments in the genome of an organism can be carried out using specially designed "molecular scissors", which are essentially endonucleases. There are 4 types of such nucleases: meganucleases, zinc finger nucleases (zinc fingers or ZNF, Kim et al., 1996) [2, 17], TALEN nucleases (Transcription Activator-like Effector Nucleases, Sanjana et al., 2012) [2 ,17], and the CRISPR-Cas system (Clustered Regularly Interspaced Short Palindromic Repeats, Cong et al., 2013) [2,17]. The first genomic editing method appeared in 1996 and was based on the zinc finger method. With the opening in 2012-2013. CRISPR/Cas genetic engineering method, fundamentally new possibilities for manipulations at the genome level of higher organisms have appeared. The method turned out to be simple and accurate when acting on specified DNA regions, which means that it could be used in almost any modern molecular biological laboratory [2]. Using the CRISPR/Cas system, any changes in the genome can be carried out: including point mutations and new genes in a certain region, deleting large sections of nucleotide sequences, correcting or replacing individual sections of genes [18, 19].

The use of the CRISPR/Cas method in combination with cell technologies opens up fundamentally new possibilities for the pathogenetic treatment of any human diseases [20]. Genome editing can be carried out at the embryonic level, which will save it from hereditary diseases. However, editing the human genome is an ethical problem, and this largely hinders the development of this method [21].
Another promising area of genetics in collaboration with cell technologies is the possibility of growing organs for transplantation [22]. All over the world, work is underway in this direction and there are already first successes.
This is how human lungs were grown at the University of Texas. And a team of scientists from Columbia University Medical Center (New York) obtained for the first time in the world a functional lung with a perfused and healthy vascular system in rodents ex vivo [22]. Bioengineers at the University of Michigan have grown a piece of mouse heart tissue. The Israeli biotechnology company Bonus BioGroup, using a three-dimensional bone model, has grown the bones of rodents [22]. Scientists from the Children's Medical Clinical Center in Cincinnati (Ohio) have grown three-dimensional structures of the human stomach using embryonic stem cells [22]. Japanese scientists have grown an eye in a Petri dish, which contains all the main layers of the retina [22]. Genentech Corporation has grown the prostate [22]. Swiss scientists from the University of Zurich have grown human heart valves from stem cells found in amniotic fluid [23]. Scientists from the University of Zurich (Switzerland) and the University Children's Hospital have grown human skin with blood and lymph vessels [23]. Scientists from the Australian University of Queensland have grown kidneys from skin stem cells [23]. Biologists from several countries at once (Japan, America and Russia) announced that they were able to grow a full-fledged analogue of the liver, capable of purifying the blood of toxins and performing other functions of this organ [23]. A group of American scientists have grown human bladders, ready for transplantation, from samples of patients' own tissues [23]. Currently, the technology of growing and transplanting organs is extremely limited in its use in humans, but progress in this area is extremely encouraging.
And finally, genetics makes it possible to study the development programs of a living organism, including aging and death, which makes it possible to develop technologies for prolonging active longevity. According to modern genetic theories, aging is the result of the accumulation of a critical level of mutations in somatic cells (mutation theory), or is associated with the loss of most of the genetic material due to a decrease in telomerase activity (telomere theory), or with the work of certain genes that program apoptosis (the theory of programmed of death). There are about 100 theories of aging in total, and most of them are explained by genetic mechanisms [24].
Very popular theories are those based on the Hayflick limit. The group of these theories includes the telomeric theory put forward by A.M. Olovnikov. He suggested that cell aging is associated with a shortening of the telomeres of the chromosomes of somatic cells with each division, due to the absence of the enzyme tandem-DNA polymerase (telomerase) in them. When the telomeres become short enough, DNA polymerase will no longer be able to replicate the ends of the DNA molecule. The process of apoptosis, the programmed self-destruction of the cell, is switched on, which explains the existence of the limiting number of divisions for the cells of the human body – 52 divisions (the Hayflick number) [24]. However, A.M. Olovnikov stopped only on theoretical assumptions, moreover, a little later he abandoned his views. However, who inspired the theory of A.M. Olovnikova, Elizabeth Blackburn, Carol Greider, and Jack Szostak discovered the mechanism for limiting DNA replication by shortening telomeres and the enzyme telomerase, for which they were awarded the Nobel Prize in Physiology or Medicine in 2009 [24]. Theoretical assumptions of genetics already now allow the development of new methods for the treatment and prevention of human involutional diseases, prolonging the active long-term.
Conclusion
The development and implementation of genetic methods in scientific and practical medicine significantly expands the capabilities of scientists and doctors. Modern higher medical education of a competitive specialist is impossible without obtaining genetic knowledge. The training of a doctor of any specialty requires not only knowledge and skills in the field of propaedeutics of clinical genetics, but also the formation of genetic testing skills, including molecular genetic testing of the patient, the ability to interpret its results, diagnose, prescribe treatment and monitor its effectiveness.