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CHAPTER
1
Homeostasis and Development
of Homeostats
1.1
HOMEOSTASIS
This book attempts to highlight some aspects of computational
Physiology and with their help, analyze diseases affecting human beings
like Cancer, Leukemia, Kidney diseases and diseases related to the
heart with the help of Computational Physiology. The analysis, interalia,
includes modelling of the internal processes, simulations thereof,
classification and development of diagnostic tools. All these diseases,
in turn, are related to and governed by various homeostat processes
in the body which are continuously in operation. Homostasis process
refer to the body ability to Physiologically regulate its inner environment to ensure stability in response to fluctuations in the outside
environment & weather. The process of homeostasis itself has been
modelled in this book using feedback control system concepts with
their homeostats (forward path), transduction paths (feedback paths)
and signaling pathways. After the modelling, other techniques of
computational biology, including simulations, are applied wherever
necessary. Hence, a study of the process of homeostasis becomes
necessary at the outset. Once this process is understood, the
application of computational Physiology to the outputs will follow
naturally.
Homeostasis is the property of a system, especially a living
organism, to regulate its internal environment and maintain a pseudostatic condition by means of multiple dynamic equilibrium
adjustments, controlled by interrelated regulation mechanisms. The
term was coined in 1932 by Walter Cannon from the Greek words
homo (same, like) and stasis (to stand, posture). Essentially, all body
tissues and organs perform functions that help maintain these near
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Modelling of Homeostasis in Computational Physiology
constant conditions [1, 2]. For instance, the lungs provide oxygen to
the extra cellular fluid to replenish the oxygen used by body cells; the
kidneys maintain ion concentrations of chemicals and the pancreas
controls the insulin levels to maintain blood glucose levels within
limits. Functionally, homeostasis is similar to feedback control system
in Engineering. Homeostat is the controller that sustains the process
of homeostasis and get their inputs through stimuli from various
sensors and body parameters.
Some examples of body parameters are pH of blood/cellular
fluids, specific gravity of urine etc. The feedback loop of the
homeostat handles the transduction phase (to be discussed subsequently) in order to trigger appropriate response from the controlling
organ. Neurotransmitters and receptors activate the signaling
pathways and convey information therein. Such closed loop systems
control various parameters of the body in different timeframes.
Normal homeostasis control and regulates with the help of chemicals,
enzymes, hormones and proteins etc in the internal environment of
the body. During signal transduction, such homeostatic processes
involve genes and their expressions. Homeostasis at this level can be
termed gene homeostasis. Typical examples of gene homeostasis are the
processes of phosphorylation and dephosphorylation.
The human body is some sort of a social order of about 100
trillion cells organized into different functional structures some of
which are called organs. Each functional structure contributes its
share to the maintenance of homeostatic conditions in the extracellular
fluid (fluid surrounding cells) which is called the internal environment
of the human body. As long as normal conditions are maintained in
this internal environment, the cells continue to live and function while
contributing their share to maintenance of homeostasis. This
reciprocal interplay (sustenance of cells and their contribution) ensures
continuous automaticity of the body until one or more functional
systems lose this ability [1]. The extra cellular fluid that constitutes
the internal environment for the homeostats is part of the body fluid
system. Fig. 1.1 shows the body fluid system comprising water
inside the body cells (cellular water), interstitial fluid (or tissue fluid
which bathes and surrounds the cells of multi-cellular organisms like
human beings) and the blood plasma. Body fluids account for 50 to
70% of body weight. Blood plasma, in turn, comprises blood in
arteries and veins and the fluid in capillaries. The extracellular fluid
is made up of blood plasma and interstitial fluid (about 21% of body
weight) [1, 2].
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Homeostasis and Development of Homeostats
Cellular water
Interstitial water
(4.5%)
(16%)
(30–40%)
28 L
11 L
2.8 L
(1–3%)
Transcellular water
TOTAL BODY FLUIDS (50 to 70% of Body weight)
Plasma
water
Fig. 1.1: Body fluids
A more compartmentalized representation of body fluids is shown in
Fig. 1.2.
RBC
CELL WATER
36%
25 L
PLASMA WATER
4.5%
3L
INTERSTITIAL
FLUID
COMPARTMENT
11.5%
8L
BONE
3%
2L
ECF
24%
17L
DENSE CONNECTIVE
4.5%
3L
TRANSCELLULAR WATER
1.5%
1L
Fig. 1.2: Compartmentalized representation of body fluids
In the Figs., % represent fluid weight as portion of body weight,
L is Litres in volume, RBC is Red Blood Cells in blood and ECF is
Extra Cellular Fluid.
A typical homeostat that maintains the pH of blood around the
value 7.4 with its forward and feedback path is shown in Fig. 1.3.
This model is the control system representation of the process with
the typical forward and feedback paths. Control system transfer
functions (G(s) and H(s) for forward and feedback paths respectively)
can be used to simulate the model. Kidney is the controlling organ
that gets the inputs from respiratory oxygen to activate the acid base
buffer systems [5, 6].
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Modelling of Homeostasis in Computational Physiology
Kidneys
Respiratory
oxygen
+
–
pH homeostat
G(s)
Output
(pH of blood - 7.4)
Transduction phase
H(s)
Fig. 1.3: Typical homeostat
A homeostat is required to project the physiological activities (normal
and abnormal) of the internal environment in the concerned area of
the model wherein the homeostatic regulation is present in the
subject. The transduction phase is responsible for the feedback which
can be negative or positive (in multiple psychosomatic disorders and
other systems where both positive and negative feedbacks coexist - in
a living system, positive feedback cannot be functional alone). Thus,
the subject may undergo different transduction processes under
normal and abnormal conditions of the internal environment.
Depending upon the nature of transduction phases, a system can be
classified as conservative or dissipative. A dissipative system diverges
from its original state by going through successive stages during
which the response decreases exponentially (which is characteristic of
many physiological systems). A conservative system, in contrast, has
an output characterized by exponentially rising phases. In many
respects, the homeostat along with its transduction phase can be
linked to the dissipative structure theory [3, 32] of Ilya Prigogine
(Belgian Scientist, Nobel Laureate for Chemistry in 1977). This linkage
will be explained in more detail in Chapter 2.
While Fig. 1.3 represents a simple homeostat, a large number of
homeostats are in operation in the human body on a continuous
basis with a very close interplay between them. A slightly more
complex cellular homeostasis model involving more than one homeostat is shown in Fig. 1.4. This model simulates pH homeostasis and
cell signalling pathway reflected in Capacitance Relaxation
phenomenon [5, 40], discussed in Chapter 4 in respect of malignant
cells.
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Homeostasis and Development of Homeostats
External stimuli
Biofeedback
homeostat
Calcium/Phosphate
homeostat
pH & Cell signalling
homeostat
Temperature
homeostat
EPO homeostat
Fig. 1.4: pH homeostasis and cell signalling pathway—malignant cells:
general block diagram
The model in Fig. 1.4 is used to describe relations between
cellular pH, VEGF (Vascular Endothelial Growth Factor, a growth
factor that leads to formation of tumours) and NRF2 (the nuclear
factor activating the antioxidant) in the case of breast cancer cases [5].
In this model, the pH homeostat that controls the pH value of
cellular fluids acts as the central module along with the cellular
signaling pathway, influenced by four others – Calcium/Phosphate
homeostat, Erythropoietin (EPO) homeostat, temperature homeostat
controlled by hypothalamus and the generalized biofeedback
homeostat that gets stimuli from external world. Cellular homeostasis
in Fig. 1.4 uses MATLAB computes simulation technique on two
homeostats models shown in Fig. 1.5. The first one gets input from
the experimental results of Capacitance Relaxation phenomenon [40]
and simulates the relation between cellular pH and VEGF. The output
of the first homeostat (pH versus VEGF) is fed to a second one
which simulates the relation between pH and NRF2. From this
output, it is possible to classify breast cancer, as ER (Estrogen
Receptor) type and non ER type [5, 6, 7]. All these homeostats along
with some others will be discussed subsequently in this chapter.
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Modelling of Homeostasis in Computational Physiology
Fig. 1.5: Simulation of cellular homeostasis in breast cancer cells
1.2
THE PHYSIOLOGICAL BACKGROUND OF HOMEOSTASIS
As brought out in section 1.1, each functional structure or system in
the human body contributes its share to the maintenance of
homeostasis in the internal environment. Some of the major systems
in this category are listed in succeeding paragraphs. Almost all the
homeostats is active in all the systems are similar to Fig. 1.4.
Blood Circulatory System: This system controls the transport of
extra cellular fluid through all parts of the body in two stages. The
first stage is the movement of blood in the blood vessels. The second
stage is movement of fluids between blood capillaries and
intercellular spaces between tissue cells. This process provides oxygen
and nutrients to cells through a process of diffusion and maintains a
near complete homogeneity of the extra cellular fluid throughout the
body, again through the process of diffusion. Figure 1.6 shows this
human circulatory system [1].
Supply of Nutrients to Cells: During their functional life, cells
use oxygen and need replenishment continuously. Lungs supply
oxygen by capturing it during breath intakes and supplying to cells
through diffusion (by molecular motions through pores of alveolar
membranes and walls of tissue capillaries). Intestines absorb nutrients
like carbohydrates, fatty acids and amino acids from ingested food
and supply them to body tissues through extra cellular fluid of the
blood. Many of the absorbed substances cannot be used as such. The
liver changes the chemical composition of these substances to a more
usable form and stores them for use by tissues as and when needed.
The musculoskeletal system (motor control element) derives its energy
from tissue cells [1].
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Homeostasis and Development of Homeostats
Jugular vein
(also subclavian
vein from arms)
Carotid artery
(also subclavian
artery to arms)
Head and arms
O2
CO2
Pulmonary
artery
Pulmonary
vein
Lungs
Superior
vena cava
Aorta
Inferior
vena cava
Heart
Hepatic
vein
Mesenteric
arteries
Liver
Hepatic
portal vein
Digestive tract
Renal artery
Renal vein
Kidneys
Iliac artery
Iliac vein
O2
CO2
Trunk and legs
Fig. 1.6: Human circulatory system
Removal of Metabolic Waste (or End Products): This is another
important function that uses homeostasis extensively. This system is
also referred to as acid base balance system. Removal of carbon
dioxide by blood and lungs deals with carbonic acid. Kidneys form
the other major waste disposal system that removes most other
substances that are end products of metabolism and not wanted by
(and thereby harmful to) the body. The wastes are disposed off
through urine and stool [1].
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Modelling of Homeostasis in Computational Physiology
Regulation of Body Functions: Nervous system. The human
nervous system [1, 2] is mainly formed of the spinal cord and brain
and is generally referred to as the Central Nervous System (CNS).
The portion of CNS that controls most visceral functions of the body
(functions related to viscera or internal organs of the body, especially
in chest and abdomen regions) is the autonomic nervous system which
is capable of changing visceral functions rapidly and intensely (in few
seconds). The autonomic system operates at a subconscious level to
control many functions of internal organs including the level of
pumping activity of the heart, movement of intestinal tract and
secretion by many of the body’s glands. The autonomic nervous
system is activated mainly by centres located in spinal cord, brain
stem and the hypothalamus. The different autonomic signals are
transmitted to various organs through two major sub divisions –
sympathetic and parasympathetic nervous systems. The nervous system in
which homeostasis plays a major role is composed of three major
parts – the sensory input portion, the central nervous system (CNS or
integrative portion) and the motor output portion. Sensory organs are
eyes, ears, nose, mouth and skin. The CNS sends out appropriate
signal to control motor functions. The functional unit of the nervous
system is the neuron. The CNS contains more than 100 billion
neurons. The communication occurs through the release of transmitter
substance into the synapses triggered by an ionic mechanism and the
signal passes through axon. A typical nerve cell is shown in Fig. 1.7.
Axon
Synapse
e
Nerv e
ls
impu
Cell body
Expanded
below
Acetylcholine
receptor
Post-synaptic
membrane
Synaptic
vessels
Extracellular
coating
Acetylcholine
Acetylcholine
sterase
Fig. 1.7: Nerve cell or neuron
Homeostasis and Development of Homeostats
9
Brain. The brain, along with the spinal cord is the communication network centre (nerve centre in common parlance) of CNS. It is
an adaptive (if a portion is damaged, other sections can take over
and adapt to look after the functions affected) central information
processor (like a computer) with processing power, memory, decision
making capability and a myriad of input/output channels. The
conscious part of the brain, the cerebral cortex, controls the sensory
activity. The subconscious part, the cerebellum, controls the motor
activity in coordination with another part of the brain known as
basal ganglia (which controls complex patterns of muscle movements).
The cerebral cortex (conscious part) never functions alone but always
in association with lower centres, the subconscious part. In fact, the
lower centres initiate wakefulness in the cerebral cortex and perform
vegetative functions. Notably, the hypothalamus in the lower centres
controls sympathetic and parasympathetic stimulation [1]. Brain
activity is controlled mainly by secretion of two types of neurotransmitters (elements that transmit signals in nervous system)–
Acetylcholine (cholinergic) and Catecholamine (adrenergic). Adrenergic
and cholinergic receptors in the autonomic nervous system have
complementary functional roles. For instance, de-activation of
sympathetic innervations by adrenergic receptors is followed by
enhancement of parasympathetic stimulation in smooth muscles by
cholinergic receptors; noradrenergic enhancement is diminished by
cholinergic neurotransmission [16]. Neurotransmitters can be
excitatory, inhibitory or both. Acetylcholine is both excitatory and
inhibitory and its effect starts decaying after the age of 60.
Epinephrine, norepinephrine, serotonin and dopamine comprise the
catecholamines whose effect is life long. Epinephrine and norepinephrine (Adrenalin and noradrenalin) are excitatory neurotransmitters
that excite the membrane of the receiving neuron. Serotonin functions
as an inhibitory neurotransmitter (that does not excite the membrane
of receiving neuron). Dopamine is excitatory in some cases and
inhibitory in others [1, 16].
Sympathetic and parasympathetic nervous systems. Depending on
the nature of stimulation of neurotransmitters, the nervous system is
also classified into two groups namely sympathetic and parasympathetic nervous systems. Sympathetic Nervous System (SNS) is
always active at a basal level (called sympathetic tone) and becomes
more active during times of stress. The parasympathetic nervous system
(PSNS) is a division of the autonomic nervous system (ANS), along with
the sympathetic nervous system (SNS) and enteric nervous system (ENS or
“bowels NS”). Stimulation of sympathetic nervous system causes large
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Modelling of Homeostasis in Computational Physiology
quantities of adrenalin and noradrenalin to be released into the
circulating blood which carries them to all parts of the body. For this
reason, sympathetic neurotransmitters are also known as adrenergic
receptors. The adrenergic receptors include α (alpha) and β (beta)
categories. Alpha receptors control physiological activities like
vasoconstriction, iris dilation, intestinal relaxation, sphincter
contraction, pilomotor contraction and bladder sphincter contraction.
In effect, alpha receptors are conservative. Beta receptors, on the
other hand, control vasodilation, cardio-acceleration, increased
myocardial strength, intestinal and uteral relaxation, bronchodilation,
calorigenesis, glycogenesis, lipolysis and bladder wall relaxation.
Blood pressure transduction phases involve both α and β receptors
linked with systolic and diastolic phases [11–13]. Beta receptors are
dissipative in nature.
Kidneys. The two kidneys play important roles in homeostasis.
Each human kidney contains about one million nephrons, each
capable of forming urine (See Fig. 7.15). Each nephron contains
glomerulus, a tuft of capillaries, through which large amounts of fluid
are filtered from the blood, and a long tubule in which the filtered
fluid is converted into urine on its way to the pelvis of the kidney.
The main functions of the kidneys are:
(i)
To rid the body of waste materials that are either ingested or
produced as a result of metabolism.
(ii)
To control the volume and composition of the body fluids. For
water and virtually all electrolytes in the body, the balance
between intake (due to ingestion or metabolic production) and
output (due to excretion or metabolic consumption) is maintained
in large parts by the kidneys. This regulatory function of the
kidneys maintains a stable environment of the cells necessary for
them to perform their various activities. Under the umbrella of
main functions (i) and (ii) above, the multiple functions
performed by the kidneys are [1]:
(a) Excretion of metabolic waste products and foreign chemicals: The
products include urea (resulting from the metabolism of
amino acids), creatinine (resulting from muscle creatine),
bilirubin (the end products of hemoglobin breakdown) and
metabolites of various hormones.
(b) Regulation of water-electrolyte balances: For maintenance of
homeostasis, the kidneys maintain a precise match between
intake and excretion.
Homeostasis and Development of Homeostats
11
(c) Regulation of acid-base balance: The kidney controls the acidbase (alkali) balance by excreting either acidic or basic urine.
Excretion of acidic urine reduces the amount of acid in extra
cellular fluid whereas excretion of basic urine removes a
base from the extra cellular fluid. In this way kidney
maintains pH homeostasis of a subject. The kidneys are the
only means for eliminating from the body certain types of
acids generated by metabolism of proteins, such as sulfuric
acid and phosphoric acid.
(d) Regulation of arterial pressure: The kidney plays a dominant
role in long term regulation of arterial pressure by excreting
variable amounts of sodium and water. The kidneys also
contribute to a short-term arterial pressure regulation by
secreting vasoactive substances such as renin that lead to
formation of vasoactive products (e.g., angiotensin II).
(e) Regulation of calcitriol: The kidneys produce active form of
vitamin D, 1,25-dihydroxy vitamin D 3 that is known as
calcitriol. Calcitriol is essential for normal calcium deposition
in bone and calcium absorption by the gastrointestinal tract.
( f ) The kidneys synthesize glucose from amino acids and other
precursors during prolonged fasting, a process referred to as
gluconeogenesis. The kidneys’ capacity to add glucose to the
blood during prolonged periods of fasting rivals that of the
liver.
(g) Regulation of erythrocyte production: The kidneys secrete
erythropoietin (EPO), which stimulates the production of red
blood cells. One important stimulus for secretion of EPO by
kidneys is hypoxia. In people with kidney disease or who
have had their kidneys removed and have been placed on
hemodialysis, severe anemia develops as a result of decreased
erythropoietin production.
(h) All the blood vessels of the kidneys, including the afferent
and the efferent arterioles, are richly innervated by
sympathetic nerve fibers. Strong activation of the renal
sympathetic nerves releases norepinephrine and epinephrine
that constrict the renal arterioles and decrease renal blood
flow and glomerular filtration rate (GFR). In general, blood
levels of these hormones parallel the activity of the
sympathetic nervous system; thus norepinephrine and
epinephrine have little influence on renal hemodynamics
except under extreme conditions, such as severe hemorrhage.