Peptide Self-Regulation of Living Systems (Facts and Hypotheses) - Shataeva L. K. 2003

Introduction

Currently, the Structure, supramolecular Organization, and Functions of the most vital components of living Cells (Peptides, Proteins, CARBOHYDRATES, Lipids, and Nucleic Acids) have been studied in detail; The Role of inorganic substances in cellular physiology is well established; the relationship between genetic coding and METABOLISM/35.html">Protein Biosynthesis has been thoroughly explored; and the MOLECULAR MECHANISMS OF Cell proliferation, differentiation, and apoptosis are under active investigation. In other words, a solid scientific foundation for understanding The phenomenon of life has already been established.

To a large extent, the advancement of numerous fields in biology, biochemistry, and genetics is driven by medical challenges—such as hormone or enzyme replacement therapy; boosting the body's immune defense during viral, microbial, or stress-induced conditions; and treating Genetic Disorders. At the same time, extensive data have been accumulated indicating that the body possesses intrinsic reserves to overcome adverse external influences and recover from pathological states. Consequently, modern medicine places special emphasis on studying the phenomenon of Homeostasis¹ across all Structural levels of living matter: the cellular, organ, and organismal levels. Living systems possess an astonishing ability to adapt to environmental changes while preserving the constancy of their internal milieu and core functions, which is The Essence of self-regulation.

The term "self-regulation" is multifaceted and encompasses, among other things, THE CONCEPT OF feedforward and feedback loops between a System and Its environment via specific signaling networks. For instance, self-regulation in automated control systems, economics, and cybernetics operates according to a program externally modified by a programmer. Such external programs function reliably as long as environmental shifts have been adequately anticipated. In contrast, self-regulation in biological systems is driven by endogenous adjustments to the program (including the genetic program) based on incoming information about environmental changes. Problems such as translating these changes into signals, perceiving those signals, and generating appropriate organismal responses are investigated through the Methods of biophysics, biochemistry, physiology, and medicine. However, these individual sciences do not yet provide a complete picture of the mechanisms that coordinate the diverse functions and reactions of an intact living Organism across various Levels of organization.

Unlike technical (artificial) systems, all developmental processes in biological systems are fundamentally irreversible, characterized by a distinct vector "from simple to complex," and utilize self-Replication mechanisms to consolidate the structures and functions attained at each evolutionary stage. It was previously hypothesized that "the progressive evolution of organisms is built on certain General Principles: polymerization, i.e., an increase in the number of homogeneous components; differentiation, i.e., the diverse specialization of these components; and integration, i.e., the coordination and unification of their functions within an integral organization." Furthermore, "...the combination of the linear Structure of Nucleic Acids with protein bodies and the maintenance of a mobile equilibrium within a relatively stable system evidently signified The Emergence of a new quality—the capacity for self-replication as the foundation of life processes. Only in this way could a multitude of similar individualities be continuously generated, serving as material for the Selection of faster-growing, more stable systems with a more precise self-replication mechanism. This underlies the ORIGIN AND EVOLUTION of living beings. At the same time, regulatory mechanisms maintaining a state of mobile equilibrium manifest themselves even within the most elementary life processes, present even in The Simplest Living Organisms. The simplest regulatory mechanism is the reversible chemical reaction, whose action can be visualized as a closed cycle of synthesis, degradation, and resynthesis" (Schmalhausen, 1961, p. 106). Quantitative confirmation of this biological concept emerged later, in the 1970s.

The second half of the 20th century was marked by an exceptional intensity in The Development of theoretical foundations in the exact sciences. First and foremost, the question of their precision was re-evaluated. Epistemology had inherited from the 19th century the dogma regarding the role of observation in science: it was assumed that the observer's actions did not alter the course of events. The development of atomic and quantum physics in the 20th century demonstrated that any observation inherently constitutes a perturbation and affects the course of events. Therefore, we can judge most phenomena and processes at the atomic and molecular scales only with a certain degree of probability. "In the life sciences, the fact is rapidly establishing itself that any observation perturbs the observed object and that the external world cannot keep its objective structure unchanged" (Brillouin, 1966, p. 83). It is worth noting that physicians and physiologists have long adhered to this viewpoint.

A number of foundational works are dedicated to the self-organization of living evolving systems (Eigen, Schuster, 1982; Caplan, Essig, 1986). For nearly half a century, the Thermodynamics of non-equilibrium systems, pioneered by I. Prigogine, has been under active development. The work of his school established the conditions under which order and self-organization emerge in open systems that exchange matter and energy with their environment. Investigations into periodic Chemical Reactions led these researchers to explore the evolution of macromolecules (Eigen, Schuster, 1982). They successfully analyzed cyclic processes in Catabolism and developed a mathematical model of the Lac Operon's operation. Thus, a pathway was outlined for analyzing regulatory processes in biologically excitable media and establishing a hierarchy of dynamic structures at THE CELLULAR LEVEL (Caplan, Essig, 1986).

Concurrently, The Theory of nonlinear oscillations and solitary waves (solitons) emerged within mathematical physics and was proposed for modeling various biological functions (Filippov, 1990). In particular, the soliton equation of motion was utilized to describe the GENERATION AND PROPAGATION of nerve impulses, as well as collective excitations in the $\alpha$-Helical structures of protein macromolecules and the Translation of ATP Hydrolysis energy along the peptide chain (Davydov, 1984).

Simultaneously, in the field of theoretical biochemistry, P. Mitchell first introduced the Concept of the vectorial nature of biochemical reactions and, on this basis, developed the chemiosmotic theory of membrane transport (Mitchell, 1976). He regarded the gradients of electrochemical potentials of chemical groups located along the transfer pathway as the driving force of transport. It is worth adding that his ideas of membrane Asymmetry and vectorial biochemistry were adopted very slowly by proponents of classical biochemistry, finding application primarily in Embryology and Cytology.

To date, molecular biology and genetics have reached a high level of technological sophistication, enabling the manipulation of individual genes, the Determination of the 3D structures of proteins consisting of hundreds of Amino Acids, and their targeted genetic-engineering biosynthesis (Metzler, 1980; Ivanov, Berlin, 2000).

Nevertheless, all these achievements do not fully explain why evolutionary biological processes exhibit such overwhelming dynamics and unwavering stability, which compel natural scientists and philosophers to elevate the thin layer of fragile and mortal creatures to the rank of geological or even planetary-scale phenomena (Vernadsky, 1988). One may hypothesize the existence of an intrinsic, inextricable interconnection between the open evolving system and its non-equilibrium environment—a link that is still overlooked in biological (and especially molecular-biological) theories. It is precisely this interrelation that dictates the flexible program of self-regulation and self-preservation inherent in living systems.

Against the backdrop of diverse theoretical breakthroughs, a vast body of biochemical research and clinical observations has now accumulated, which not only poses fundamental questions in biology and medicine but also contributes significantly to their resolution.

By the late 1980s, views on the physiology of bioregulation had fundamentally changed. In particular, as I. P. Ashmarin notes, "our understanding of the mechanisms of synaptic transmission underwent a qualitative shift, revealing it as an arena of complex interactions between classical Neurotransmitters and regulatory peptides. Compared to other Intercellular signaling systems, the peptide system proved to be the most numerous, and the peptide regulators themselves turned out to be particularly pleiotropic and multifunctional. A conceptual framework emerged regarding a functional continuity—a regulatory continuum consisting of peptides and coupled intercellular signaling molecules of a different nature" (Ashmarin, Kamenskaya, 1988).

Clinical and biochemical studies indicate that a remarkably wide spectrum of bodily functions is regulated precisely by oligopeptides and peptides,² which are frequently (and inaccurately) referred to as Peptide Hormones. The effective concentrations of these substances within living cells are so low that their quantitative participation in metabolism is ruled out. P. K. Klimov proposed a signaling mechanism for peptide regulation based on the tuning fork–resonator principle, where regulatory peptides (RPs) act as the tuning fork (Klimov, Barashkova, 1993). The operation of this mechanism is somewhat analogous to that of Nervous system neurotransmitters. However, while Nerve Impulse generation relies on electrochemical action upon the synaptic membrane, the physicochemical mechanisms underlying the signaling action of peptides on The Cell membrane remain incompletely understood. Examining a large body of experimental research from a dual perspective—considering both the PHYSICOCHEMICAL PROPERTIES OF peptides and the Regulation of Specific physiological functions—brings the correlation between Peptide Structure and biological activity into sharp focus. Biomedical investigations into the therapeutic effects of RPs have revealed that they exhibit a distinct type of regulation known as tissue-specific modulation. The established mechanism of receptor-mediated signal Transduction into the cell operates on an "on–off" switch principle, where the intensity of the response to a signal is not graded. In contrast, the REGULATORY EFFECTS OF peptides are milder and more prolonged: they modulate—that is, alter according to a specific temporal pattern—the intensity of pre-existing functions within a differentiated tissue to maintain its normal state.

² In this paper, in accordance with modern conventions (by analogy with oligonucleotides), the term "oligopeptides" will be used to designate short peptide chains containing from 2 to 10 amino acid residues; the term "peptides" for chains consisting of 10–20 amino acid residues; and the term "Polypeptides" for peptide chains containing more than 20 amino acid residues. Unlike proteins, peptides and polypeptides generally do not adopt a tertiary structure in solution and do not undergo irreversible Denaturation.

The absence of an RP Classification based on structure and specific activity has led to the proliferation of several generalizing yet imprecise terms. For instance, the term "kinins" was proposed for a broad group of single-chain polypeptides, which included angiotensins, bradykinins, and secretin. Later, the term "cytokines" emerged to denote a group of proteins secreted by one cell type that act on specific receptors of other cells (Yarilin, 1999), eliciting diverse responses in the target cells. Polypeptides secreted by lymphocytes were named lymphokines; those secreted by Cells of the mononuclear phagocyte system were termed monokines, and so forth. Currently, cytokines are defined as humoral regulators—Glycoproteins operating at pico- and nanomolar concentrations that influence the growth and differentiation of individual Cells and Tissues. This group includes interferons, interleukins, tumor necrosis factors, growth factors, etc. (Lyashchenko, Uvarov, 2001). The Diversity of their structures, physicochemical properties, and physiological manifestations, compounded by toxicity during clinical application, complicates the classification of these endogenous regulatory macromolecules according to their in vitro specific activity.

A special Class of BIOREGULATORS is formed by tissue-specific peptides known as cytomedins (Morozov, Khavinson, 1983, 1996); a number of studies have drawn comparisons between cytomedins and cytokines (Khavinson, Zhukov, 1992; Kuznik et al., 1999). According to the proposed classification, every normal differentiated tissue synthesizes and secretes in small quantities into the humoral environment its own specific peptides—cytomedins. On the one hand, these peptides control the functions of that tissue; on the other hand, they serve as molecular signals informing the entire organism that the tissue is functioning normally, thereby suppressing potential compensatory mechanisms for specific functions (Khavinson, Zhukov, 1992).

Certain properties of cytomedins—their tissue Specificity, lack of species specificity, and ability to inhibit proliferation—align them with endogenous regulators of the chalones class. However, cytomedins possess lower molecular weights and exhibit greater stability in the humoral environment.

Work on the isolation, characterization, clinical trials, and widespread medical application of cytomedins has been underway for over 30 years. Although in an academic sense the duration of study is not a definitive measure of scientific validity, in practically oriented fields (such as clinical practice) it generally correlates with the number of independent replications and verifications. Cytomedins feature a relatively simple structure, allowing their oligopeptide analogs obtained via chemical synthesis to exhibit the same activity and tissue specificity as natural preparations (Kuznik et al., 1999).

Until recently, The problem of tissue specificity was viewed strictly at the macro-level; in other words, RPs were isolated from specific Organs and tissues while ignoring the cellular heterogeneity comprising each organ. Modern histochemical methods have proven the existence of a diffuse neuroendocrine cell system within the body—the APUD system (named after the acronym for Amine Precursors Uptake and Decarboxylation). Its specific functions include the uptake and decarboxylation of precursors, as well as the synthesis of biogenic amines such as melatonin and histamine (Raikhlin et al., 1993). Furthermore, these cells produce a broad spectrum of RPs dedicated to local self-regulation within differentiated tissues and the humoral transmission of organ status signals to the Central Nervous System.

Comparing regulatory peptides isolated from various tissues with those derived from the Brain revealed not only structural similarities (Homology of oligopeptide blocks and characteristic alternation of hydrophilic and hydrophobic side chains) but, in several cases, complete identity. P. K. Klimov emphasized the integrative significance of brain peptides in maintaining the body's overall homeostasis: "The brain constantly synthesizes and contains, with few exceptions, all regulatory peptides, which provided grounds to designate the brain as a major endocrine organ" (Klimov, Barashkova, 1993, p. 80). This explains the vast number of studies focused on analyzing and synthesizing brain peptides for medical Applications aimed at restoring impaired functions and systemic self-regulation. For practical medicine, synthetic peptides are attractive because they are structurally identical to natural endogenous regulators (or represent their modifications), cause minimal side effects, and are highly accessible for large-scale production.

Looking at The Study of brain peptides from another angle—that of epistemology—reveals a significant departure from the standard scientific experiment structured around a "question–answer" scheme. This human endeavor is directed not merely toward "objective reality given to us in sensations," but rather toward comprehending the molecular mechanisms underlying our own thinking, reflection, memory, and behavior.

When a biochemist analyzes the chemical structures of brain peptides, evaluates them, and attempts to decipher their MECHANISM OF ACTION, their own intellectual efforts are made possible by that very same mechanism. This is an instance of a living system interacting with its environment (an interaction not yet accounted for theoretically). Striving for self-identification, the continuum of Neuropeptides and Transmitters actively participates in constructing an internal representation of both the external environment and the self within it. Reflection at this level functions less as a psychological phenomenon and more as an epistemological tool. Without self-identification—that is, without The ability to separate oneself from the environment and distinguish between "self and non-self," "part and whole," or "property and its measure"—the self-regulation of an open system is impossible, whether it is a multifunctional macromolecule or an organism at a high stage of evolution.

Self-awareness elevates humanity's primitive notions of health—traditionally based merely on the absence of illness—to the level of conscious self-preservation. Transforming from an eternal combatant against nature, including its own nature, human beings become mindful custodians of their bodies. Consequently, self-regulation, which exists at the level of unconscious, genetically programmed molecular mechanisms, can be augmented by a conscious and deliberate strategy for preserving health and maintaining homeostasis under stress or Aging. By securing adequate scientific information through intellectual and social integration, humans as a biological species acquire adaptive capacities far beyond those provisioned by the natural genetic program.

The foregoing explains why our work focuses primarily on the Structure and properties of peptides—those informational molecules that integrate multiple functions within the compact architecture of a polypeptide chain. Specifically, they perceive environmental and internal shifts, generate information signals, transmit them to cells, establish feedback loops, and thereby sustain the organism's self-regulation.

Synthesizing these data through the application of physical chemistry and thermodynamics, and leveraging these insights, directs medical biochemistry and pharmacology toward the development of novel RP-based therapeutics designed to restore the vital functions of traumatized or aging organisms.