In this issue of the Journal (pp. 617–623), Bates and colleagues introduce us to the concept of percolation (1), used as a means to link the progression of the anatomic pathology of diffuse lung disease to the resulting functional abnormalities. Percolation is a mathematical approach to the behavior of random networks. It was originally developed in the 1950s to describe the movement of fluids through porous materials. Percolation networks are distinguished by a phase change when a threshold number of network elements are connected or fractured. For example, for a liquid to percolate through porous materials, a series of channels through which the liquid flows must open. An interconnected series of pathways develop, but nothing much happens until the pores reach the other side and the liquid can successfully flow through the material. At this point, a qualitative change occurs and the whole nature of the system enters a new phase where there is nothing to stop the flow of liquid from one side to the other. Similarly, redirection of electrical current due to localized transmission failure can overstress other parts of the grid, such as occurred on August 14, 2003, when a blackout developed throughout the northeast United States and southern Canada. Percolation has been applied to diverse fields, to predict the likelihood of successful oil drilling, the spread or extinction of epidemics and forest fires, the evolution of social fads or species, and growth of capillaries in tumors.

To our knowledge, this is the first time percolation theory has been applied to lung diseases. Yet, the application is highly apt. The stiffening of individual springs to simulate fibrosis does very little to the overall lung elastic properties until they span the network in three dimensions. This occurs when about 65% of the springs are stiffened. At that point, the network exhibits an abrupt phase change with the sudden increase in lung stiffness. The percolation of the pathogenesis of emphysema initially involved the random cutting of springs as analogous to loss of alveolar tissue. Because alveolar walls are under tension, their loss must increase the tension in remaining walls leading to an accelerating cascade of failures. The model of emphysema also reaches “a phase change around a critical threshold” when only 15% of the springs are cut, and the elastic recoil of the network falls to zero (1).

What does a “phase change” around a “critical threshold” mean? A phase change occurs during the transition of water to ice and the critical threshold is a temperature of 0°C. Over a very small temperature change, there is a profound change in the nature of water. In complex systems, like life, phase transitions are increasingly found where phenomena emerge that can neither be predicted nor understood by examining the component parts in isolation.

It appears that life itself exists in a phase transition, as if balanced precariously between solid and liquid (2, 3). Living things are open thermodynamic systems that import energy from the environment and export waste products into it. We exist somewhere in the continuum between the near-equilibrium, linear, frozen thermodynamic systems of crystals and the evanescent, nonlinear, far-from-equilibrium systems like weather (2). It is only through metabolic energy expenditure that we are able to sustain our threshold state. We thereby remain relatively stable in form, yet adaptable to new conditions without profound change in our phenotype. We achieve this with multiple feed-forward loops, resulting in nonlinear behavior that is mitigated by negative feedback loops that prevent our systems from running away with themselves (2, 4). This energy-utilizing complex system of checks and balances keeps us at the statistically unlikely phase transition between ice and water (2).

A phase transition seems to be a peculiar place to live. Why is this our place in the grand scheme of things? The answer is that it is only in the phase transition that the conditions necessary for survival, adaptability, and evolution are found. The living exist in the phase transition between crystals and weather because that is the only place we can exist.

We are learning that disease also leads to phase transitions that can be unwelcome. Exploring disease as an alteration in our thermodynamic state is long overdue. If we live at a critical threshold, then relatively minor perturbations of the threshold point may cause major phenotypic changes. What is the threshold that preserves health? Our best guess is that it is the distance we live from thermodynamic equilibrium, determined by the metabolic rate of our body tissues. If so, ischemic disease shifts us too close to equilibrium, whereas inflammatory disease pushes us in the opposite direction. But, in addition to metabolic rate, Stuart Kauffman reminds us that the nature and number of interconnections among component parts is also crucial (4). We communicate within our bodies in many different ways: by hormones, cytokines, chemotaxis, nerves, or, in the present context, by strands of lung parenchyma. If so, there is probably a connection between the energy we dissipate and the number and nature of our interconnections, because the amount of energy dissipated and the nature and number of interconnections both play a crucial role in whether we function in chaotic, weatherlike, and complex or highly ordered crystalline states (2, 4). In Kauffman's view, we are complex, poised on the edge of chaos (4). If so, disease has the capability of completing the phase transition one way or the other.

Approaching disease in this way is in its infancy. The application of percolation to the progression of parenchymal lung diseases by Bates and colleagues (1) is a major step in the right direction. Both emphysema and pulmonary fibrosis lead us into unwelcome phase completions, emphysema in one direction to complete loss of recoil and fibrosis in the other direction, to excessive lung recoil. Living in a phase transition implies that our lungs are in dynamic balance between collagen and elastin synthesis and absorption, poised between two opposite completed phases, either of which would result in death. When the balance tips, the percolation starts. Unless the balance is redressed, we exit the phase transition and enter into the new and unwelcome phase of illness.

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