4 The Body: an Open System with an Internal Environment(continued b excretion of waste and foreign substances, physiology have been established only in ex- and the skin for the release of heat. The kidney ceptional cases nd lungs also play an important role in regu- si content, osmolality, ion concentrations, ph onto and eg hich is achieved by convective transport or ng distances (circulation, respiratory tract), controlled variable such as the blood pressure moral transfer of information(hormones ). ubject to selective external modification, and transmission of electrical signals in the for example, through alteration of the heart 日 nervous system, to na These mechanisms are responsible for supply also affect the blood ure and heart rate and disposal and thereby maintain a stable in. the controlled variable can only be kept rnal environment. even under conditions tant by continuously measuring the current lood pressure, comparing it with the refer. survival in the sense of preservation of the recting any deviations. If the blood pressure oecies. Important factors in this process in- drops-due, for example, to rapidly standing clude not only the timely development of roductive organs and the availability of fertil- will increase until the blood pressure has been able gametes at sexual maturity, but also the reasonably adjusted. Once the blood ontrol of erection, ejaculation, fertilization, has risen above a certain limit, the heart rate and nidation. Others include the coordination will decrease again and the blood pressure will of functions in the mother and fetus during normalize. This type of closed-loop control is process called a negative feed back control sys control dircuit(C1). It consists of a controller he centra ous system(CNS)processes with a programmed set-point value(target signals from peripheral sensors (single value)and control elements(effectors)that can sensory cells or sensory organs), activates out- adjust the controlled variable to the set point. ardly directed effectors (e.g, skeletal The system also includes sensors that continu- uscles ) and influences the endocrine glands. ously measure the actual value of the cor The CNS is the focus of attention when study- trolled variable of interest and report it(feed- ng human or animal behavior. It helps us to lo- back) to the controller, which compares the ac- cate food and water and protects us from heat tual value of the controlled variable with the cold. The central nervous system also plays a set-point value and makes the necessary role in partner selection, concern for offspring justments if disturbance-related discrepancie n long after their birth, and integration into have occurred. The control system operates cial systems. The CNS is also involved in the either from within the organ itself (autoregula- evelopment, expression, and processing of tion)or via a superordinate organ such as the motions such as desire, listlessness, curiosity, central nervous or hormone gland wishfulness, happiness, anger, wrath, and Unlike simple control, the elements of nvy and of traits such as creativeness, inquisi- trol circuit can work rather imprecisely tiveness, self-awareness, and responsibility. without causing a deviation from the set p This goes far beyond the scope of physiology- (at least on average). Moreover, contre functions of the body-and, hence, of this book. turbances. In the case of blood pressure regu- Although behavioral science, sociology, and lation (C2). for example, the system can re psychology are disciplines that border on spond to events such as orthostasis (p. 204) hysiology, true bridges between them and or sudden blood loss
4 1 Fundamentals and Cell Physiology excretion of waste and foreign substances, and the skin for the release of heat. The kidney and lungs also play an important role in regulating the internal environment, e.g., water content, osmolality, ion concentrations, pH (kidney, lungs) and O2 and CO2 pressure (lungs) ( B). The specialization of cells and organs for specific tasks naturally requires integration, which is achieved by convective transport over long distances (circulation, respiratory tract), humoral transfer of information (hormones), and transmission of electrical signals in the nervous system, to name a few examples. These mechanisms are responsible for supply and disposal and thereby maintain a stable internal environment, even under conditions of extremely high demand and stress. Moreover, they control and regulate functions that ensure survival in the sense of preservation of the species. Important factors in this process include not only the timely development of reproductive organs and the availability of fertilizable gametes at sexual maturity, but also the control of erection, ejaculation, fertilization, and nidation. Others include the coordination of functions in the mother and fetus during pregnancy and regulation of the birth process and the lactation period. The central nervous system (CNS) processes signals from peripheral sensors (single sensory cells or sensory organs), activates outwardly directed effectors (e.g., skeletal muscles), and influences the endocrine glands. The CNS is the focus of attention when studying human or animal behavior. It helps us to locate food and water and protects us from heat or cold. The central nervous system also plays a role in partner selection, concern for offspring even long after their birth, and integration into social systems. The CNS is also involved in the development, expression, and processing of emotions such as desire, listlessness, curiosity, wishfulness, happiness, anger, wrath, and envy and of traits such as creativeness, inquisitiveness, self-awareness, and responsibility. This goes far beyond the scope of physiology— which in the narrower sense is the study of the functions of the body—and, hence, of this book. Although behavioral science, sociology, and psychology are disciplines that border on physiology, true bridges between them and physiology have been established only in exceptional cases. Control and Regulation In order to have useful cooperation between the specialized organs of the body, their functions must be adjusted to meet specific needs. In other words, the organs must be subject to control and regulation. Control implies that a controlled variable such as the blood pressure is subject to selective external modification, for example, through alteration of the heart rate ( p. 218). Because many other factors also affect the blood pressure and heart rate, the controlled variable can only be kept constant by continuously measuring the current blood pressure, comparing it with the reference signal (set point), and continuously correcting any deviations. If the blood pressure drops—due, for example, to rapidly standing up from a recumbent position—the heart rate will increase until the blood pressure has been reasonably adjusted. Once the blood pressure has risen above a certain limit, the heart rate will decrease again and the blood pressure will normalize. This type of closed-loop control is called a negative feedback control system or a control circuit ( C1). It consists of a controller with a programmed set-point value (target value) and control elements (effectors) that can adjust the controlled variable to the set point. The system also includes sensors that continuously measure the actual value of the controlled variable of interest and report it (feedback) to the controller, which compares the actual value of the controlled variable with the set-point value and makes the necessary adjustments if disturbance-related discrepancies have occurred. The control system operates either from within the organ itself (autoregulation) or via a superordinate organ such as the central nervous system or hormone glands. Unlike simple control, the elements of a control circuit can work rather imprecisely without causing a deviation from the set point (at least on average). Moreover, control circuits are capable of responding to unexpected disturbances. In the case of blood pressure regulation ( C2), for example, the system can respond to events such as orthostasis ( p. 204) or sudden blood loss. The Body: an Open System with an Internal Environment (continued) Urinary substances, acid–base disturbances, hypertension
Control and Regulation I 5 C. Control circuit t va ctualya set point Controller Negative feed back Actual value Control circuit: principle Disturbance Actual pressure NerveⅨ Presso. 2 Control circuit: blood pressure orthostasis etc
51 Fundamentals and Cell Physiology Plate 1.2 Control and Regulation I " $%% # $& % ' $ % ( ! " ) % * % & % * %! & ' + ! & , ( ! - & & ' ' &!&
6 The Body: an Open System with an Internal Environment(continued b The type of control circuits described Oscillation of a controlled variable in re- keep the controlled a disturbance variable can be rhen disturbance variables cause the con- tenuated by either of two mechanisms. First trolled variable to deviate from the set sensors with differential characteristics (D D2). Within the body, the set point is rarely sensors)ensure that the intensity of the sensor 2 ecessary. In this case. it is the variation of the set point(p.314 ff.).Second, feedforward set point that creates the discrepancy between control ensures that information regarding the w the nominal and actual values, thus leading to expected intensity of disturbance is reported Since the regulatory process is then triggered trolled variable has changed at all. Feedfor by variation of the set point (and not by distur- ward control can be explained by example of t bance variables), this is called servocontrol or physiologic thermoregulation, a process in stment of muscle length by muscle spindles terregulation before a change in the controlled nd y-motor neurons (p. 318)are examples value( core temperature of the body)has actu- of servocontrol ally occurred (p. 226). The disadvantage of n addition to relatively simple variables having only d sensors in the control circuit can uch as blood pressure, cellular pH, muscle be demonstrated by example of length, body weight and the plasma gluco (-pressoreceptors) in acute blood concentration, the body also regulates com- pressure regulation. Very slow but steady plex sequences of events such as fertilization, changes, as observed in the development of pregnancy, growth and organ differentiation, arterial hypertension, then escape regulate as well as sensory stimulus processing and the In fact, a rapid drop in the blood pressure of a motor activity of skeletal muscles, e.g. to hypertensive patient will potentially cause maintain equilibrium while running. The regu- counterregulatory increase in blood pressure. latory process may take parts of a second (e.g, Therefore, other control systems are needed to purposeful movement) to several years(e.g. ensure proper long-term blood pressure regu- the growth latior In the control circuits described above. the led variables are kept co ge, with variably large, wave-like deviations. The sudden emergence of a disturbance varia le causes larger deviations that quickly ne nalize in a stable control circuit (E, test sub- ect no. 1). The degree of deviation may be The latter is true, for example, for the blood ucose concentration, which nearly doubles fter meals. This type of regulation obviously Inctions only to prevent extreme rises and falls(e.g. hyper- or hypoglycemia)or chronic deviation of the controlled variable. More pn cise maintenance of the controlled variable re. uires a higher level of regulatory sensitivity ends the settling time (E, subject no. 3)and tion where the actual value oscillates back and forth between extremes(unstable oscillation, E, subject no. 4
6 1 Fundamentals and Cell Physiology The type of control circuits described above keep the controlled variables constant when disturbance variables cause the controlled variable to deviate from the set point ( D2). Within the body, the set point is rarely invariable, but can be “shifted” when requirements of higher priority make such a change necessary. In this case, it is the variation of the set point that creates the discrepancy between the nominal and actual values, thus leading to the activation of regulatory elements ( D3). Since the regulatory process is then triggered by variation of the set point (and not by disturbance variables), this is called servocontrol or servomechanism. Fever ( p. 226) and the adjustment of muscle length by muscle spindles and γ-motor neurons ( p. 318) are examples of servocontrol. In addition to relatively simple variables such as blood pressure, cellular pH, muscle length, body weight and the plasma glucose concentration, the body also regulates complex sequences of events such as fertilization, pregnancy, growth and organ differentiation, as well as sensory stimulus processing and the motor activity of skeletal muscles, e.g., to maintain equilibrium while running. The regulatory process may take parts of a second (e.g., purposeful movement) to several years (e.g., the growth process). In the control circuits described above, the controlled variables are kept constant on average, with variably large, wave-like deviations. The sudden emergence of a disturbance variable causes larger deviations that quickly normalize in a stable control circuit ( E, test subject no. 1). The degree of deviation may be slight in some cases but substantial in others. The latter is true, for example, for the blood glucose concentration, which nearly doubles after meals. This type of regulation obviously functions only to prevent extreme rises and falls (e.g., hyper- or hypoglycemia) or chronic deviation of the controlled variable. More precise maintenance of the controlled variable requires a higher level of regulatory sensitivity (high amplification factor). However, this extends the settling time ( E, subject no. 3) and can lead to regulatory instability, i.e., a situation where the actual value oscillates back and forth between extremes (unstable oscillation, E, subject no. 4). Oscillation of a controlled variable in response to a disturbance variable can be attenuated by either of two mechanisms. First, sensors with differential characteristics (D sensors) ensure that the intensity of the sensor signal increases in proportion with the rate of deviation of the controlled variable from the set point ( p. 314 ff.). Second, feedforward control ensures that information regarding the expected intensity of disturbance is reported to the controller before the value of the controlled variable has changed at all. Feedforward control can be explained by example of physiologic thermoregulation, a process in which cold receptors on the skin trigger counterregulation before a change in the controlled value (core temperature of the body) has actually occurred ( p. 226). The disadvantage of having only D sensors in the control circuit can be demonstrated by example of arterial pressosensors (= pressoreceptors) in acute blood pressure regulation. Very slow but steady changes, as observed in the development of arterial hypertension, then escape regulation. In fact, a rapid drop in the blood pressure of a hypertensive patient will potentially cause a counterregulatory increase in blood pressure. Therefore, other control systems are needed to ensure proper long-term blood pressure regulation. The Body: an Open System with an Internal Environment (continued) Control circuit disturbance, orthostatic dysregulation, hypotension
Plate 1.3 Control and Regulation ll 7 D. Control circuit response to disturbance or set point (SP)deviation 2 Controller D Controller stem Disturb- Disturb- Set poi Actual value 1 Stable control 2 Strong disturbance 3 Large set point shif E. Blood pressure control after suddenly standing erect 70 Slow and incomplete (deviation from set point) 100 Unstable control
71 Fundamentals and Cell Physiology Plate 1.3 Control and Regulation II -. . /. 0. 1. 2. 3. 4. -.. 5. 4. -.. 5. 4. 3. --. -.. 5. 4. 4. 31 3. 21 " 6 " * 7 % ( ) * ) + , - 8 * * &9 - * &9 * &9 / * &9 0 ( ( :; 7 , * % ( ! 6 "* & #* & .< % * * " &= * * 6 &= $ % ! !& +$,
The cell The cell is the smallest functional unit of ger RNa(mRNA)is responsible for ism. In other words, a cell (and no code transmission, that is, passage of coding maller unit)is able to perform essential vital sequences from DNA in the nucleus(base functions such as metabolism, growth, move- sequence) for protein synthesis in the ent, reproduction, and hereditary transmis- (amino acid sequence)(C1). mRNa is ion(W Roux)(p 4). Growth, reproduction, formed in the nucleus and differs from DNA in g by cell division it contains ribose instead of deoxyribose, and ell components: All cells consist of a cell uracil (U)instead of thymine In DNA, each cytoplasm(ca 50 voL%), amino acid (e., glutamate, -E)needed for and membrane-bound subcellular structures synthesis of a given protein is coded by a set of nown as organelles (A, B). The organelles of three adjacent bases called a codon or triplet eukaryotic cells are highly specialized. For in- (C-T-C in the case of glutamate ) In order to ascribe the DNA triplet, centrated in the cell nucleus, whereas"diges- complementary codon (e. g, G-A-G for gluta- es are located in the lysosome xidative ATP production takes place in the (tRNA)molecule is responsible for reading the mitochondria. odon in the ribosomes(C2). tRNA contains he cell nudeus contains a liquid known a complementary codon called the as karyolymph, a nucleolus, and chromatin. for this purpose. The anticodon for glutamate hromatin contains deoxyribonucleic acids is C-U-C(E). (DNA), the carriers of genetic information. Two RNA synthesis in the nucleus is controlled trands of DNA forming a double helix (up to by RNa polymerases(types I-lll) Their effect 7 cm in length) are twisted and folded to form on dNAis hromosomes 10 um in length. Humans nor- tein. Phosphorylation of the polymerase oc- ve 46 chromosomes, consisting of 22 curs if the repressor is eliminated (de-repres- pairs and the chromosomes that sion)and the general transcription factors at- the sex(XXin females, XY in males). tach to the so-called promoter sequence of the IA is made up of a strand of three-part DNA molecule(T-A-T-A in the case of poly molecules called nucleotides. each of which ll). Once activated, it tes the two of a pentose(deoxyribose)molecule, a strands of dna at a particular site so that the ate group, and a base. Each sugar code on one of the strands can be read and of the monotonic sugar-phosphate transcribed to form mRNA (transcription, backbone of the strands(. deoxyribose --C1a, D). The heterogeneous nuclear RNA phosphate-deoxyribose.. )is attached to one (hnRNA)molecules synthesized by the pol of four different bases. The sequence of bases merase have a characteristic"cap"at their 5 represents the genetic code for each of the end and a polyadenine"tail"(A-A-A-.at the ghly 100000 different proteins that a cell 3' end (D). Once synthesized, they are oed"in a protein coat, DNA double helix, each base in one strand ine haters rogeneous nuclear ribonucleoprotein of DNa is bonded to its complementary base i A or pre rule: adenine mrna of hnrna contains both codi (A)with thymine(T)and guanine(G)with cy- sequences(exons)and non-coding sequences osine(C). The base sequence of one strand of (introns). The exons code for amino acid e double helix(→E is always a"mirror sequences of the proteins to be synthesized, nage"of the opposite strand. Therefore, o thereas the introns are not involved in the and can be used as a template for making a coding process. Introns may contain ew complementary strand, the informat tion 0000 nucleotides; they are removed f ontent of which is identical to that of the orig. primary mRNA strand by splicing ( inal. In cell division. this the means and then degraded. The introns, themselves, by which duplication of genetic information contain the information on the exact splicing plication)is achieved. site. Splicing is ATP-dependent and requires b
8 1 Fundamentals and Cell Physiology The cell is the smallest functional unit of a living organism. In other words, a cell (and no smaller unit) is able to perform essential vital functions such as metabolism, growth, movement, reproduction, and hereditary transmission (W. Roux) ( p. 4). Growth, reproduction, and hereditary transmission can be achieved by cell division. Cell components: All cells consist of a cell membrane, cytosol or cytoplasm (ca. 50 vol.%), and membrane-bound subcellular structures known as organelles ( A, B). The organelles of eukaryotic cells are highly specialized. For instance, the genetic material of the cell is concentrated in the cell nucleus, whereas “digestive” enzymes are located in the lysosomes. Oxidative ATP production takes place in the mitochondria. The cell nucleus contains a liquid known as karyolymph, a nucleolus, and chromatin. Chromatin contains deoxyribonucleic acids (DNA), the carriers of genetic information. Two strands of DNA forming a double helix (up to 7 cm in length) are twisted and folded to form chromosomes 10 µm in length. Humans normally have 46 chromosomes, consisting of 22 autosomal pairs and the chromosomes that determine the sex (XX in females, XY in males). DNA is made up of a strand of three-part molecules called nucleotides, each of which consists of a pentose (deoxyribose) molecule, a phosphate group, and a base. Each sugar molecule of the monotonic sugar–phosphate backbone of the strands (. . .deoxyribose – phosphate–deoxyribose. . .) is attached to one of four different bases. The sequence of bases represents the genetic code for each of the roughly 100 000 different proteins that a cell produces during its lifetime (gene expression). In a DNA double helix, each base in one strand of DNA is bonded to its complementary base in the other strand according to the rule: adenine (A) with thymine (T) and guanine (G) with cytosine (C). The base sequence of one strand of the double helix ( E) is always a “mirror image” of the opposite strand. Therefore, one strand can be used as a template for making a new complementary strand, the information content of which is identical to that of the original. In cell division, this process is the means by which duplication of genetic information (replication) is achieved. Messenger RNA (mRNA) is responsible for code transmission, that is, passage of coding sequences from DNA in the nucleus (base sequence) for protein synthesis in the cytosol (amino acid sequence) ( C1). mRNA is formed in the nucleus and differs from DNA in that it consists of only a single strand and that it contains ribose instead of deoxyribose, and uracil (U) instead of thymine. In DNA, each amino acid (e.g., glutamate, E) needed for synthesis of a given protein is coded by a set of three adjacent bases called a codon or triplet (C–T–C in the case of glutamate). In order to transcribe the DNA triplet, mRNA must form a complementary codon (e.g., G–A–G for glutamate). The relatively small transfer RNA (tRNA) molecule is responsible for reading the codon in the ribosomes ( C2). tRNA contains a complementary codon called the anticodon for this purpose. The anticodon for glutamate is C–U–C (E). RNA synthesis in the nucleus is controlled by RNA polymerases (types I–III). Their effect on DNA is normally blocked by a repressor protein. Phosphorylation of the polymerase occurs if the repressor is eliminated (de-repression) and the general transcription factors attach to the so-called promoter sequence of the DNA molecule (T–A–T–A in the case of polymerase II). Once activated, it separates the two strands of DNA at a particular site so that the code on one of the strands can be read and transcribed to form mRNA (transcription, C1a, D). The heterogeneous nuclear RNA (hnRNA) molecules synthesized by the polymerase have a characteristic “cap” at their 5′ end and a polyadenine “tail” (A–A–A–. . .) at the 3′ end ( D). Once synthesized, they are immediately “enveloped” in a protein coat, yielding heterogeneous nuclear ribonucleoprotein (hnRNP) particles. The primary RNA or premRNA of hnRNA contains both coding sequences (exons) and non-coding sequences (introns). The exons code for amino acid sequences of the proteins to be synthesized, whereas the introns are not involved in the coding process. Introns may contain 100 to 10 000 nucleotides; they are removed from the primary mRNA strand by splicing ( C1b, D) and then degraded. The introns, themselves, contain the information on the exact splicing site. Splicing is ATP-dependent and requires The Cell Genetic disorders, transcription disorders