Math! Cornput.Mode&g, Vol. II. pp.

464468, 1988 0X95-7177188

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NONLINEAR AND PHILOSOPHICAL ISSUES

IN BIOLOGICAL MODELLING

WHEN IS A MECHANISM NOT A MECHANISM? THE NETWORK THERMODYNAMIC APPROACH TO

COMPLEX SYSTEMS

D. C. Mikulecky

Department of Physiology MCV/VCU

Richmond, Virginia 23298.0551 USA

Abstract. Rosen (1985) has made a distinction between two classes of

objects, "mechanisms" and "complex systems". One central distinguishing
feature is the applicability of the Newtonian paradigm. Mechanisms are
describable with this formalism, while complex systems, such as living
systems, are not. Rosen maintains that living systems can, at best, be
given a very local description by the use of mechanisms. This
categorization is potentially very useful and can provide insight into the
dominant roles played by both empiricism and reductionism in modern biology
(Mikulecky, 1987). Reductionism is methodologically motivated by the
absence of a theory of complex systems in today's Physics and Chemistry.
Systems must be reduced to simple mechanisms in order to be tractable in
terms of the theory provided by those incomplete disciplines. Complex
systems have been most thoroughly studied in engineering. Network
thermodynamics uses theory originating in engineering and applies it in a
general way to the complexity of topological connectedness in a dynamic
system, Although it begins with elements which are obviously mechanisms in
Rosen's language, it quickly illustrates that the whole is much more than
the mere sum of its parts. This work uses multiport network elements which
represent some of the most common energy conversion processes in living
systems to rigorously establish that simple mechanisms begin to "emerge" in
the sense that the composite system can behave in new ways, none of which
are characteristics of its constituent elements. The long term goals of
these efforts are two fold: 1) to establish a network or circuit theory
for the dynamic events observed in living systems, and 2) to identify in
specific examples the transition from mechanistic to complex system
behavior.

Keywords. Complex systems, nonequilibrium thermodynamics, kinetics,

cotransport model, simulation, nonlinear systems, reference state,
biological models, reaction-diffusion systems, graph theory, networks

INTRODUCTION The Characteristics of Modern Biology

Network thermodynamics is a relatively new The characteristics of modern biology,

approach to the analysis and modeling of especially in its relation to theory and
complex systems, which was especially motivated mathematical modeling, has these salient
by those encountered in biology (Peusner, 1970, features:
1986; Oster, Perelson and Katchalsky, 1973).
Its building blocks are classical 1. An extremely strong reliance on
thermodynamics, kinetics, graph and network methodological reductionism (Peacocke, 1985).
theory. By generalizing the results of This can be attributed to the lack of
applying network and graph theory to electronic theoretical content in physical and chemistry
systems, network thermodynamics extends in the area of complex systems. Biological
thermodynamic reasoning beyond equilibrium and systems are reduced to simple mechanisms in
steady states away from equilibrium to the order to touch base with existing theory.
whole range of time dependent nonlinear
systems. Methods of network analysis have been 2. An unconscious tendency toward oncological
recognized to be general in the past "physical reductionism. That is, the use of
systems theory" (Roe, 1966). Network methodological reductionism, which has some
thermodynamics is a unifying approach which has historical justification, tends toward an
had some significant new contributions to identification of the organism with its parts.
thermodynamics. These will be summarized here This work is aimed at showing that the whole is
along with a brief description of the approach. more than the mere sum of its parts even at
fairly simple levels of organization.
First, it is worthwhile to make special notice
of the role of network thermodynamics in 3. A very strong reliance on empiricism as the
biological modeling and to relate it to Rosen's only way of knowing (Mikulecky, 1983; Fidelman
call for a theory of complex systems (Rosen, & Mikulecky, 1985). Once again, this has its
1985; Peacocke, 1983). historical roots in the absence of any
recognizable theory of complex systems and the

464
 Proc. 6th Int. Conf: on Mathematical Modelling 465

need to reduce organisms and their subsystems
to a level where the available theory lost the
essence of biological organization and
complexity.
Rosen's Distinction
Rosen (1985) distinguishes between simple
mechanisms and complex systems in a useful way.
The attributes of the two categories are
largely complimentary. Simple mechanisms are
those which fit the Newtonian Paradigm and, at
best, only locally approximate complex systems.
Three distinct causalities, material,
effective, and formal have distinct
manifestations in the mathematics. Final cause
is completely absent. Complex systems, on the
other hand, are only approximated by the
Newtonian paradigm, are anticipatory, and have
strong reliance on final cause or teleology.
The other three forms of causality are often
mixed in complex systems.
possible to go beyond the usual nonequilibrium
thermodynamics (see, for example, Katchalsky
and Curran, 1964 and Caplan and Essig, 1985) to
an incorporation of more "mechanistic" models
via network thermodynamic methods and a close
examination of the relationship of mechanistic
(thermokinetic) networks and thermodynamic
networks.
The network thermodynamic auuroach to
noneauilibrium thermodynamics.
To illustrate how the network approach sheds
new light on nonequilibrium thermodynamics, a
two degree of freedom system will be used as an
example. The results are far mare general and
extend to n degrees of freedom, although they
become much harder to visualize. The basic
formulation for isothermal systems involves the
dissipation function
Q - T(dS/dt) = Jl Xl + J2 X2, (1)

NETWORK THERMODYNAMICS AS AN APPROACH where T is the absolute temperature, S is the

TO A THEORY OF COMPLEX SYSTEMS. entropy, Ji, is the ith flow and Xi is the ith
thermodynamic driving force (i = 1,2). For the
The Explicit Recovnition of TopoloEical usual, linear treatment, the forces are linear
Contributions to Svstem's Behavior. functions of the flows. These are the
"phenomenological" equations,
Electronics uses network and graph theory to
combine the properties of the circuit elements
X1 = R11 Jl + R12 J2, (2)
with an encoding of how they are connected
together (topology). It is clear that both and X2 = R21 Jl + R22 J2. (3)
kinds of information are needed to explain why
a picture appears on a TV screen The
disconnected pile of components is not a TV Equations 2 and 3 can be algebraicly
set. Network thermodynamics extends this rearranged,
distinction into a broader class of systems and
thereby goes beyond the usual applications of Xl - (Rll - Rl2) Jl + Rl2 (Jl + J2), (4)
the Newtonian paradigm by treating topology as
something mare than mere boundary conditions. and X2 = R21 (Jl + J2) + CR22 - R21) J2. (5)
Each element in a network applies a kind of
boundary condition to each other with which it When Onsager reciprocity holds, R12 = R21, and
is in connection, but this connectedness itself there is a connected network representation of
is a property of the system. this system as shown by the dotted lines in
Figure 1. The generality of Onsager
reciprocity in the linear domain near
One other well established feature of the equilibrium is widely known. Less well known
network thermodynamic approach is that the is the relation to Tellegen's theorem (Penfield
nonlinear or even cumbersome linear problems et. al., 1970). The us& approach to
have been successfully simulated on circuit noneouilibrium thermodvnamics is to look at
simulation programs such as SPICE2 (Fidelman only the resistors in the diagram and the flows
and Mikulecky, 1986; Mintz --,
et. al. 1986; through them. By considering the flows through
Mikulecky, 1983, for example). The focus of the sources, as well, Tellegen's theorem is
the remainder of this discussion will be on obtained from the holistic approach of network
thermodynamic and kinetic modeling, to theory. Onsager's reciprocity and minimum
illustrate their relationship as networks and dissipation follow from this powerful theorem
to suggest a means by which the transition from (Peusner, 1986).
simple mechanism to complex system can be
systematically approached.

Contributions of Network Thermodvnamics to

Thermodynamics

Peusner (1986) has established a number of new

aspects of thermodynamic theory via network
thermodynamic reasoning. Some of the most
striking are the macroscopic proof of Onsager's
reciprocal relations and the establishment of a
metric structure in the mathematics, As a step
in the development of the metric reasoning, the
establishment of Kedem and Caplan's (1965)
degree of coupling as a geometric invariant and
a key factor in imbedding the affine Onsager
space in an orthogonal higher dimensional FIG. 1. The dotted lines are the network
space. Once network thermodynamics has been representation of eauations 2 and 3. The more
noted ta have these deep links and new detailed resistive network discussed below is
interpretations in thermodynamic theory, it is shown in dark lines.
466 Proc. 6th Int. Cmf. on Mathrmatical Motldling

If the phenomenological equations are Thermokinetic Networks

substituted into the dissipation function a
bilinear form results, Another class of networks arises from models of
reaction and reaction-transport systems.
0 = R11 J12 + (Rl2 + R2l) J1J2 + R22 .J2*. (6) Figure 3 is an example of a cotransport system
which couples the transport of two ligands, A
This bilinear form can be rewritten using the and B across a membrane through a complex
reciprocity condition and Kedem and &plan's formed with a common "carrier" molecule in the
(1965) degree of coupling, which is defined as, membrane. The complexes CA and CB are much
more permeable than the individual chemical
q = R12/ Rl1 R22 species A, B, or C.
(7)
Network thermodynamics provides a method for
With the substitution representing these kinetic systems as steady
state resistive networks (Peusner et. al.,
yl = Jlj% (8) 1985; Mikulecky, et. al., 1985). The procedure
is relatively simple no matter how complex the
and y2 - J2+m (9) system. One necessary step is to realize that
in the steady state, or in a series of steady
equation 6 becomes, states, a second order reaction like the
binding of the ligand to the carrier can be
0 = Y1* + q Yl Y2 + y2*. (10) represented as a pseudo first order reaction as
long as the ligand concentration is kept
The bilinear form has an affine coordinate constant. The binding reaction is,
system associated with it and the angle, 0,
between the coordinates is arccosq. Only in c + L $CL, (11)
the trivial case when q=O is the coordinate
system in two dimensions orthogonal. This is where L stands for either ligand A or ligand B.
when the two subsystems are totally uncoupled The kinetics are second order for the forward
and independent. In this formalism, each two (binding) reaction,
degree of freedom system has an intrinsic
affine coordinate system associated with it and JF = KF(C)(L), (12)
therefore, there is no common "metric" or
measure of length as in an orthogonal system,
Here the length of the vector associated with Q but can be represented as a pseudo first order
is dependent on the angle or degree of reaction for any constant value of L,
coupling.
JF - KL(0, (13)
Figure 2 shows that the affine two dimensional
coordinate system is easily imbedded in a three where
dimensional orthogonal system. Now, all two
degree of freedom systems have a common metric, KL - KF(L). (14)
independent of their degree of coupling. The
imbedding simply requires that the origin be Given this, the construction of a network for
common to both systems and that the affine such situations is straight forward. The
plane be tilted upward an amount depending on general first order kinetic step
the degree of coupling. The three orthogonal
coordinates are simply determined bv the three A + B, (15)
resistors in the network reuresentation (Figure
1, see Peusner's work for details). is
J = &B(A) - KBA(B). (16)
A simple factoring out of KAB puts the right
hand side into the form of a conductance times
a potential difference which can be represented
by a simple resistor in Figure 1.

J = KAB[(A)-(KBA/KAB)(B)I. (17)

Using this procedure in an iterative fashion,

the system has the network representation in
Figure 1. Under certain experimental
conditions the resistances in the network are
true constants and the network's solution is,

Y
X1 = Rll JI + R12 J2 (18)

x X2 = R21 J1 + R22 J2. (19)

These equations are good for any given

FIG. 2. The affine coordinate svstem
in an orthogonal system.
imbedded reference state (Sauer, 1973; Mikulecky, et.
al., 1985). For example, hold each ligand
constant on one side of the membrane. Vary the
driving forces by manipulating the ligand
concentrations on the other side. There are as
number of other permutations and combinations
as well. They are isomorphic with the
equations of nonequilibrium thermodynamics in
 Proc. 6th Int. Conf. on Mathematical Modeiling 467

It has been demonstrated that nonequilibrium

thermodynamics has its counterpart in
CA,- CA R resistive, multiport networks. This
recoenition leads to an orthorronal coordinate
system and a metric for meas&ng distance
between states. When a more model dependent
approach involving kinetics is used, the
situation becomes analogous if the problem of
the reference state is taken into account.
Under these conditions, the model dependent
thermokinetic networks have a form isomorphic
with the thermodynamic networks and merge
smoothly into them near equilibrium. The most
important conclusion to be drawn from the
network thermodynamic analysis of systems is
that their topology or connectedness is a
property of the system and not merely a set of
boundary conditions. Moreover, these
topological characteristics have much to do
with the distinction between simple mechanisms
and complex systems.

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