Biomedical Engineering Reference
In-Depth Information
havior. In comparison, models in physics and chemistry are robust and reliable
because the physical laws are very well known and hold under a wide range of
conditions. By its nature, mathematical modeling requires prior knowledge of all
the factors and conditions that affect a reaction or, by extension, a system. For
small, well-isolated systems some/most of the information can be obtained in
vitro, but it is extremely hard to imagine all possible factors that impact a given
phenomenon. Added to this is the computational constraint, especially if
the model is based on stochastic methods. Due to a lack of adequate data, there
will always be a problem of unknown components contributing to non-intuitive
results.
2. The cell is more like a gel than a soupy bag of enzymes and substrates.
Thus the in-vitro rate constants obtained from aqueous solutions do not perfectly
match the description of real intracellular environments. Furthermore, gradients,
compartments, and inhomogeneous mixtures of substances arise in the cyto-
plasm. Models commonly assume well-mixed environments to avoid mathe-
matical and computational complexities.
3. The rate constants are mostly assumed and/or extrapolated from experi-
mental results. Even when data are available, there is always an inherent varia-
tion regarding the organism and the experimental protocols.
4. A mechanistic model is purely data driven and incorporates a large num-
ber of parameters, the values of which are not always possible to obtain with
accuracy. To overcome this limitation, parameter-finding algorithms are used
that try to find a parameter value closest to its in-vivo counterpart. However, if
the search space is large the accuracy of such predictions can be limited.
5. In many cases the reaction kinetics is completely unknown.
6. Temporal inactivation or degradation of enzymes is not generally consid-
ered in kinetic models.
7. Metabolic channeling is the movement of substrates between several ac-
tive sites in a multi-enzyme complex (37) within a co-localized environment.
Since it is a special case of metabolism where anatomical separation of a path-
way is important, the global/local impact of such molecular crowding is pres-
ently unclear.
8. The time scales of intracellular transactions vary from 10
-6
seconds (dif-
fusion) to many hours (gene regulation). Thus, it is difficult to choose an ideal
time step for concurrent simulation of gene expression, diffusion, metabolism,
and signal transduction.
9. Complex systems show a collective behavior of individual components,
more commonly known as emergent phenomenon, i.e., the whole is greater than
the sum of its parts. The real behavior of a cell cannot be guessed merely by
looking at individual components. At the moment it is unclear at what step we
should stop adding complexity to the system beyond which it becomes redun-
dant.
