Nonlinear network theory of complex diseases
University of Vermont
Last modified: July 28, 2006
Many common diseases are described as “complex”, being characterized by multi-factorial etiologies, widely varying prognoses, and unclear therapeutic options. Complex diseases invariably seem to involve an inappropriate or over-exuberant manifestation of some normal bodily function, such as the homeostatic failure of hypertension, the uncontrolled cellular proliferation of cancer, and the chronic inflammatory state that characterizes asthma. Another general characteristic of complex diseases, apart from their resistance to elucidation, is that they are chronic; the homeostatic balance of health seems to become disrupted in a permanent way that cannot be reversed with treatment. Given that a living system can be viewed as a dynamic network, albeit an enormously complicated one, we address the general question of what could cause a complex dynamic network to exhibit abnormal behavior for an extended, or even indefinite, period of time. We identify three ways: 1) alteration of network structure, 2) a persistent noxious input, and 3) transition to a “non-normal” stable state. The first two possibilities are obvious. The third possibility, however, is more subtle and arises because the energy landscape of a nonlinear dynamic network may have multiple local minima. We show that a biologically motivated Hopfield-type network in which the nodal activation functions follow Michaelis-Menton kinetics can have multiple minima, and that transition between minima can be achieved with a suitable external stimulus. This suggests that chronic diseases may result from an environmental insult that moves a living network from its state of health to one of permanent pathology. This would occur with no change in network structure, so there would be nothing to repair. Furthermore, searching for the initiating event, which could be long gone at the time of diagnosis, would also be futile. The enigmatic nature of a pathology of this kind would thus make its correction especially problematic, which could explain why complex diseases are so often idopathic and such a challenge to treat.