© 2004 American Thoracic Society
Cell and Molecular Biology Is not the Only Way to a Better Understanding of Pathogenesis of Lung DiseaseMeakins Christie Laboratories McGill University Health Centre Research Institute Montreal, Quebec, Canada The argument that "only cell and molecular biology can lead to an understanding of pathogenesis of lung disease" is a statement in a form analyzed extensively by the philosopher, Karl Popper (1). "For Popper, a theory is scientific only if it is refutable...Every genuine test of a scientific theory...is logically an attempt to refute or to falsify it, and one genuine counter-instance falsifies the whole theory"(2). It follows that a single example of understanding pathogenesis of lung disease arising out of research that is neither cell nor molecular biology suffices to show that the "pro" statement of this debate is wrong. This makes my task easy, but first let us see what the word pathogenesis means. The Dictionary of Science and Technology (3) has two definitions: "Medicine: the source or development of a disease or disease process," and "Cell biology: the cellular events and reactions occurring during disease development." (3). I, of course, will discuss the former definition. If Dr. Snider were to insist on the cell biological definition, I would concede defeat, but because this is a journal of medicine, what we are discussing here is the medical definition. Let's start with examples of purely physiological research that have revealed the pathogenesis of lung disease processes. Excessive bronchoconstriction is a sine qua non of asthma. This mechanical event involves airway smooth muscle (ASM) activation with resulting force, displacement, and energy dissipation. The activation is likely supramaximal (4–6) and, if so, excessive bronchoconstriction cannot be caused by excessive agonist. The degree of airway narrowing (and thus the severity of many asthmatic attacks) is determined by the force generating capacity of ASM relative to the load on which ASM acts (7, 8). Thus, the pathogenesis of excessive bronchoconstriction is due either to an increased force developed by asthmatic ASM or a decreased load or both. Normally, this balance is modified by the effects of breathing and deep inspirations, which keep ASM dilated in a state of perturbed equilibrium (8, 9). In asthma, however, an increased velocity of shortening may allow stretched ASM to shorten too quickly thereby abolishing the potent bronchodilatation of breathing (10, 11). Virtually everything we know about the pathogenesis of excessive bronchoconstriction is the result of research in classical Newtonian mechanics. In COPD, exercise limitation is arguably the most important pathophysiologic abnormality. It is the reason why patients with COPD become disabled. Its pathogenesis in some patients is due to dynamic hyperinflation and dyspnea (12); in others, it is due to skeletal muscle dysfunction and leg fatigue (13); in yet others, inadequate energy supplies to locomotor and respiratory muscles is the cause (14, 15). Virtually everything we know about the pathogenesis of exercise limitation in COPD is the result of research in exercise physiology. According to Popper, I could rest my case, but I will not because it is important to understand why knowledge of pathogenesis of many diseases (not just disease processes) will never depend entirely on cell and molecular biology. Physiology deals with discovering how living things become ordered. Medicine seeks to understand disorders. Living things obey the laws of physics (although these laws may not explain everything about life) (16). The physical law pertinent to the development of order and disorder is the second law of thermodynamics (17). This law states that systems in thermodynamic equilibrium become progressively more disordered with time. In physical terms: their "entropy" inexorably increases. Conversely, as systems move progressively away from thermodynamic equilibrium by dissipating more and more energy, entropy production decreases; hence, order must increase. All living things are far from thermodynamic equilibrium because we consume and dissipate energy by metabolism. The stunning order we display is a fundamental feature of life (17–19), a result of our metabolic rate that determines how far we are from thermodynamic equilibrium. Metabolism is responsible for both the development and maintenance of life's order (17). What do we know about the cause and effect relationship between metabolic rate of tissues, organs, and systems, and their highly ordered structures and functions? Precious little (16)! Not much more than what is described in the previous paragraph. Granting agencies, while focusing on molecular biology and genetics, have hardly been proactive in fostering research on the development and maintenance of order, even though it is of great importance to medicine. With such a vague knowledge of how our bodies become ordered, we cannot possibly understand the pathogenesis of disorders. There is a caveat here: there is an important difference between the physical meaning of disorder and the medical one. In physics, disorder or entropy production increases as living systems move closer to thermodynamic equilibrium and their metabolic rate decreases. An increase in entropy production is equivalent to changing from a statistically improbable state to a statistically more probable one. Thus, metabolism normally maintains statistically improbable configurations in our bodies. What happens when metabolic rate is excessive and we are too far from thermodynamic equilibrium? These states produce medical disorders, too, but in this instance, the "disease" is no longer associated with statistically more probable states. Asthma is an interesting example. The increased metabolic rate of ASM, when activated, causes airway narrowing and configurations of the tracheobronchial tree that are statistically highly improbable in the normal lung (10). When described in terms of physics, asthma is a disease with too little entropy production, statistically rare states of the airways, and, thus, excessive order! A medical "disorder" can result from increased physical "order". It is imperative that this distinction between medical and physical meanings of "disorder" be understood. Be that as it may, I hope the moral is clear. We will never completely understand pathogenesis until we know how tissues, organs, and systems become deranged when they function too far from or too close to thermodynamic equilibrium, and entropy production becomes too small or too great. Cell and molecular biology may help, but research using tools of thermodynamics, statistical mechanics, and complexity hold the key that will unlock these great secrets of life, health, sickness, and death. FOOTNOTES Conflict of Interest Statement: P.T.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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