Molecular Pathology

Antoni Horst

• Publisher: CRC Press
• Year: 2018
• ISBN:
  9781351091671
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Molecular Biology
• Index: Biological Sciences

This book provides modern views of developments in medical sciences based on advances in molecular pathology. Topics discussed include the molecule; the genome of eukaryotes and its function; gene regulation; the proteins; molecular aspects of inflammation, immunology, and carcinogenesis; molecular biology of the nervous system; molecular defects in the endocrine system; molecular diseases of the blood and blood-forming tissues; and diagnosis of molecular diseases. Four tables and 75 figures illustrate the concepts and provide a quick means to reference important data. Immunologists, pathologists, geneticists, and all other researchers in the biological and medical sciences will find a wealth of information in this ground-breaking new book.

Chapter 1

INTRODUCTION

The origin of disease has aroused remarkable human interest from the dawn of history. Primitive man believed that illnesses are caused by environmental pathogenic factors. To the primitive man it was difficult to believe that a disease could be caused by idiopathic somatic disturbances, and therefore he ascribed its origins to various insignificant environmental factors, such as cold, fatigue, famine, troubles, etc. or even to the action of supernatural factors, such as malicious pagan gods. On the other hand, he believed that good health was a gift of good-natured gods.

In general, the more sober were views upon life at a given era, the more rational were views about the causes of disease. Therefore, the reasonable ancient thinkers noticed some kind of somatic causes of disease: Hippocrates, in his humoral theory of disease, taught that an unbalanced composition of body fluids (dyscrasia) was the main cause of disease, and Asklepiades, in his atomic theory of disease, viewed the main cause as the malformed structure of body components (atoms).

Because of the mystical views about life in the Middle Ages, beliefs that disease is caused by God as a kind of punishment for sins, etc. re-emerged.

In the following centuries, when strict thinking became dominant, living organisms were considered as a kind of complicated machine, composed of relatively simple components, which principally did not differ from artificially constructed machines. After the discovery in the early 19th century (first in plants and later in animals) that cells were the principal body constituents of all living organisms, Virchow, in the middle of the 19th century established his well-known cellular theory of disease. This theory was the prevailing theory up to the middle of the 20th century.

Soon, however, it became obvious that this theory could not explain many aspects of life processes and, consequently, various illnesses. In fact, this theory was nothing more than a theory which transposed the living phenomena from the whole organism to the same living phenomena restricted to the cells. Consequently, all incomprehensible living phenomena were related to a mysterious vital function. In other words, the ancient vitalistic view of life processes was revived.

The vitalistic character of the cellular theory, although not able to provide a final resolution of vital processes, enabled man to acquire an enormous amount of knowledge in the field of many physiological and pathological processes.

In the period of the “cellular theory” many extraorganismic causes of disease were recognized. The most important findings in this field were the great microbial discoveries at the end of the 19th century, when recognition of pathogenic microbes seemed to be identical with the recognition of causes of the particular disease. Consequently, an increasing number of erroneous beliefs proposed that illnesses were principally caused by noxious environmental factors.

There were many objections to this doctrine. For instance, Rene Dubos named this trend as “a doctrine of specific etiology of diseases” which does not take into account the specificity of living organism, although it was well known that not all species suffered from the same infectious diseases, and to find animals susceptible to some infectious diseases which occur only in man was very difficult and sometimes impossible.

The conclusion was obvious that, for the occurrence of a particular disease, an adequate susceptible living organism was necessary. Unfortunately, the general knowledge of living processes was, at that time, so unsatisfactory that it was impossible to establish a substantial theory about causes of disease (considering the extraorganismic noxious factors and the intraorganismic factors which make the organism susceptible to the disease). Therefore, despite the noted progress in many branches of medical science, the fundamental resolution of the essence of the vital processes also was impossible.

Correct views of the life processes did not occur prior to discovery of the molecular bases of heredity and knowledge of the mechanisms of protein biosynthesis and the function of protein molecules. With these discoveries it was proven, for the first time, that specific characteristics are inherited through a chemical substance, i.e., deoxyribonucleic acid (DNA) which determines (codes) the sequence of amino acids in synthesizing protein molecules that are responsible for all vital functions. These findings made it possible to consider the dependence of disease on the presence of specific active substances in living organisms, whose normal structure and function are responsible for health, and abnormal structure and function are responsible for disease. This produced a radical change of view about the causes of disease from mainly extraorganismic to the organismic ones and, as a matter of fact, that diseases are not caused by deviation of mysterious vital processes of the whole organism but by molecules, the function of which is exclusively based on well-known physicochemical reactions.

In aspects of molecular biology, living processes occur when reacting molecules appear at an adequate place and time in the organism. Usually, many kinds of interacting molecules are necessary to initiate and maintain vital functions. At the moment when the stimulus for the life function disappears, the life function must also expire. This is accomplished by inactivation of the reacting molecules, usually by decay of these molecules. Therefore, vital function arises usually by the synthesis or activation of preexisting molecules specific for the given reaction and is terminated by inactivation of the reacting molecules. Very often the synthesized active molecules are so labile that they disintegrate almost immediately after their synthesis; in other cases their decay is caused by specific enzymes. In this aspect a vital function comes into existence by the permanent synthesis of active molecules which, almost immediately after their synthesis, disintegrate.

The permanent synthesis and decay of protein molecules (the average half-life time of proteins is 3 days) require a mechanism which always ensures the synthesis of the same molecules, otherwise continued life of a given organism would be impossible. The permanent synthesis of the same protein molecules is always defined by the genetic code. Therefore, we come to the conclusion that a normal genetic code and efficient mechanisms of synthesis of protein and other components of an organism are essential processes for life.

The purpose of this book is to present evidence about the molecular mechanisms essential for the occurrence of disease. Molecular events happen in living organisms, therefore the molecular mechanisms of disease turn from the environment to the organism, lending itself (or in combination with environmental factors) to the production of disease. It must be emphasized that the environmental factors must not be pathogenic per se, but factors which in combination with molecular defects of the organism become pathogenic. That is, in molecular biology, the causes of illnesses are to be found principally inside the living organism, and not so much in environmental pathogenic factors.

This change in concept of disease causes requires a thorough knowledge of the elements of molecular biology which enables one to interpret events leading to the occurrence of disease. These elements comprise knowledge of specific structure, synthesis, and function of molecules reacting in the living organisms. To these elements belong structure and function of genes, regulation of gene expression, mechanisms of protein biosynthesis, molecular bases of cell differentiation, mechanisms of mutations, pathological variants of proteins with disturbances of stability and function, etc.

Molecular disturbances as causes of disease usually are recognized in heritable diseases. This seems inappropriate because all protein molecules of living organisms depend on the genetic code and, as is well known, every protein molecule may undergo mutations some more often and others less often. At present our knowledge about variants of protein molecules is very limited. The best known are globin molecules, principally because of their accessibility and appearance in the erythrocytes in an almost pure state. Thanks to this example, we know many pathological health disturbances are caused by point mutation with the consequence of a single substitution of only one amino acid (e.g., sickle cell anemia is caused by the instability of the globin beta chain [erythremia] caused by increased oxygen affinity, methemoglobinopathies being unable to transport oxygen, etc.) or disturbances of globin synthesis (e.g., various kinds of thalassemias caused by gene deletion or disturbances of the particular steps of protein synthesis).

The question arises if other diseases may be caused by pathological variants of proteins. Besides pathological variants of globin, we also know some other protein variants, although these have not been studied as well (e.g., pathological variants or lack of fibrinogen and other blood clotting factors, and other blood plasma components). Variants of tissue proteins are very little known, principally because of their inaccessibility. According to the genetic rule that every gene may undergo mutations we must accept the idea that tissue proteins also are composed of an enormous number of protein variants which differ in a better and more efficient, or a less and even totally inefficient function. Only in this way can it be explained why one person is a very efficient runner and the other is not; why one person does not suffer from hypoxia in high mountains and the other does; why one person dies in his early youth because of heart failure and the other lives to old age; why one person is susceptible to an infectious disease and the other is not. There are countless such examples. The only explanation we can assume is that the cause of these differences lies in the varied quality of molecules responsible for the particular functions. Since defective functions are the essential cause of disease, it must be accepted that defective variants of protein components of living organisms are the main causes of all idiopathic diseases.

Chapter 2

THE MOLECULE: ANATOMY AND PHYSIOLOGY

I. THE STRUCTURE OF MOLECULES

A molecule is an aggregate of atoms held together by chemical bonds (strong covalent bonds and weak chemical bonds or interactions) of a definite size, structure, and function. Cells are composed of molecules which form organelles (being aggregations of molecules of specific function). The distribution of molecules inside the cell, as well as in its organelles, is not random but well-defined, which makes the very different functions of different cells possible. The arrangement of different molecules inside the cell and its organelles is controlled by weak chemical bonds. Therefore, the knowledge of these bonds is very important in understanding the role of molecules in performing vital functions.

A chemical bond is an attractive force that holds atoms together. We distinguish strong covalent bonds and weak chemical bonds. The most characteristic feature of bonds is their strength. Strong bonds never dissociate at physiological temperatures. Atoms bound by covalent bonds belong to the same molecule. Covalent bonds hold atoms closer than weak chemical bonds. For example, two hydrogen atoms bound covalently are 0.074 nm (0.74 Å) apart, while bound by weak van der Waals’ contacts are 0.12 nm (1.2 Å) apart. Atoms bound by covalent bonds are capable of weak interactions with neighboring atoms. In living cells, covalent bonds can be formed or dissociated only by the action of appropriate enzymes.

Weak bonds are very important for the function of molecules. The most important are van der Waals’ bonds, hydrogen bonds, and ionic bonds. Weak chemical bonds, also called “secondary bonds,” exist not only between atoms of the same molecule, but also between atoms of different neighboring molecules. Weak bonds can be broken easily at normal physiological temperatures, which enables some flexibility of molecules. Single weak bonds are not strong enough to bind two atoms together when present singly, but a group of weak bonds can bind atoms and even molecules also for relatively longer periods of time. The most important feature of weak bonds is that they allow movement of atoms inside the molecule. The number of covalent bonds of a given molecule is limited by its valence, while the number of weak bonds is limited only by the number of atoms which simultaneously touch each other. Single covalent bonds permit free rotation of bound atoms, while two or more bonds delimit more or less the movements of the bound atoms. In contrast, weak bonds (van der Waals’ ionic) do not restrict bound atoms.

The nature of bonds can be explained by quantum mechanics which states that all bonds, independently of their type, are based on electrostatic forces. The spontaneous formation of a bond involves release of internal energy of the unbound atoms, which is converted into another form of energy. Thus, the reaction between two atoms can be described by the formula

$\text{A}+\text{B}\to \text{AB}+\text{energy}$

where A and B represent the particular atoms, and AB the molecule. The rate of the reaction depends on the frequency of collisions between the reacting atoms. The stronger the bond, the greater amount of energy is released. The most common unit to measure energy is the calorie, and since thousands of calories are necessary to break a mole of bonds, the chemical energy for this purpose is expressed in kilocalories (kcal) or joules (J) and kilojoules (kJ) per mole (mol).

Weak chemical bonds also can break. The most important forces which cause dissociation of chemical bonds come from heat energy. Because of the kinetic energy, collisions with fast moving atoms or molecules may push apart the bound atoms. The higher the temperature, the faster the molecules are moving and the greater is the probability that in consequence of the collisions the bonds will break. Therefore, with an increase of temperature, the stability of molecules decreases. The breaking of a molecule may be described by the formula

$\text{AB}+\text{energy}\to \text{A}\text{+}\text{B}$

which denotes that energy necessary to break a bond is equal to the amount of energy released during formation of the molecule. This is in accordance with the first law of thermodynamics that energy can be neither made nor destroyed.

Very important for the living organisms is the equilibrium between formation and breaking of chemical bonds, i.e., that the amount of forming and breaking bonds is equal.

Biologically important is the so-called “free energy” of chemical reactions because it enables metabolic reactions. In biological systems free energy is the energy that has the ability to do work, represented by the symbol ΔG. According to the second law of thermodynamics, during all spontaneous reactions a decrease of free energy occurs (ΔG is negative). After reaching equilibrium no change in the amount of free energy occurs (ΔG = 0). Therefore in a state of equilibrium a closed number of atoms possesses the lowest amount of free energy.

Free energy may be transformed into heat or it increases the amount of entropy (in a simplified form entropy may be described as the amount of disorder, i.e., structure, of a molecule). Therefore, the greater the disorder (i.e., the more complicated the structure of the molecule), the greater is the amount of entropy. On the contrary, crystallization is the state where atoms are bound in a strict order. The increase of entropy during a reaction denotes that the given reaction does not liberate heat.

II. THE POLARITY OF MOLECULES

Molecules in which atoms are symmetrically distributed are nonpolar molecules, and molecules in which atoms are nonsymetrically distributed are polar molecules. The nonpolar molecules are uncharged. Electronegative atoms have the tendency to gain electrons, and electropositive atoms have the tendency to give up electrons. In a polar molecule, e.g., a water molecule (H₂O) the two hydrogen atoms are electropositive, and the one oxygen atom is electronegative. The center of the positive charge is on the one side of the molecule and the negative on the other side of the molecule. Separated negative and positive charges create an electric dipole moment. A dipole is characte...

Table of contents

• Cover
• Title Page
• Copyright Page
• Table of Contents
• Chapter 1 Introduction
• Chapter 2 The Molecule: Anatomy and Physiology
• Chapter 3 The Genome in Eukaryotes and Its Function
• Chapter 4 Gene Regulation
• Chapter 5 The Proteins
• Chapter 6 Molecular Bases of Cell Differentiation
• Chapter 7 The Molecular Structures of the Eukaryotic Cell
• Chapter 8 Mutation
• Chapter 9 The Pathology of Globin Molecules
• Chapter 10 The Molecular Aspects of Inflammation
• Chapter 11 The Molecular Aspects of Immunology
• Chapter 12 The Molecular Aspects of Carcinogenesis
• Chapter 13 Molecular Biology of the Nervous System
• Chapter 14 Molecular Defects in the Endocrine System
• Chapter 15 Molecular Diseases of the Blood and Blood-Forming Tissues
• Chapter 16 Molecular Mechanisms of Metabolic Disorders
• Chapter 17 Pharmacogenetics
• Chapter 18 Diagnosis of Molecular Diseases
• Index