Perspectives in Biology and Medicine

THE UNPREDICTABILITY OF CELLULAR BEHAVIOR: TRIVIAL OR OF FUNDAMENTAL IMPORTANCE TO CELL BIOLOGY? M. B. HALLETT* Introduction No student of science can fail to be impressed by an apparent fundamental difference between experimental physics and experimental biology . Physics is characterised by equations that explain (and control) experiments with precision and reproducibility. If the inverse-square law cannot be demonstrated in a laboratory experiment, it is the experimental technique and not the physical law that must be revised. However, experiments with biological systems are rarely expected to be precisely predictable, and irreproducibility within often wide limits is an accepted part of bioexperiments. This "biological variation" may result from parameters in the experimental situation that are not controlled, variable, or ill defined. However, techniques aimed at studying individual isolated cells under experimental conditions and external influences that are tightly controlled reveal that a major feature that persists and has become unmistakable is the unpredictability of the behaviour of responses from living cells. Even in the presence of high technological scrutiny, isolated cells refuse to behave as predictable physical units but remain as "individuals" endowed with an apparent element of choice. For example , it has long been recognized that, in a population of chemotactic cells, not all cells move in the same direction, some responding immediately to a chemotactic stimulus, some only sluggishly turning towards the stimulus, and yet others remaining apparently oblivious to the stimulus [I]. Following stimulation, the intracellular Ca2+ which triggers This essay received honorable mention in the 1988 Dwight J. Ingle Memorial Writing Award for young authors. * University Department of Surgery, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, United Kingdom.© 1989 by The University of Chicago. All rights reserved. 0031-5982/90/3301-0660$01.00 110 I M. B. Hallett ¦ Unpredictability ofCellular Behavior the cellular events may, in some cells within the population, rise sharply after stimulation, whereas in other cells in the same population it may rise only after long delays or not at all [2]. It has not been possible in any cell population to remove this type of individual heterogeneity of response despite efforts to produce cell populations that in other respects appear completely homogeneous. An individual neurosecretory cell exposed to the same stimulus repeatedly may secrete sometimes and other times not [3]. Unpredictability of response therefore appears to be an intrinsic property of individual cells. This raises an important question. Is this unpredictability the result of our inability to control and our ignorance of the appropriate parameters within the cell? If it were, this unpredictability would have an origin that is essentially trivial. However, I will attempt to persuade you that, even if we knew everything about all the relevant processes occurring within a particular cell, we would still be unable to accurately predict the behaviour of that cell. I will propose that unpredictability of cellular behaviour is an inescapable consequence of key physical and chemical events occurring within the cell. As such, it must be taken into account in any attempt to provide a complete description of the intracellular control of cellular behaviour. I will argue that, far from being trivial, the mechanisms of unpredictability underlie the need for the organisation of tissues and may play a role in some disease processes and key steps in evolution. Origin of Cellular Unpredictability The driving force for physical and chemical phenomena has long been recognised as the relentless progress towards randomness, that is, increase in entropy [4—6]. This principle of the second law of thermodynamics is supreme among all the laws of physics. Eddington, the British physicist, for example, wrote: "If someone points out to you that your pet theory ... is in disagreement with Maxwell's equations—then so much the worse for Maxwell's equations. Ifit is contradicted by observation —well these experimentalists do bungle things sometimes. But if your theory is against the second law of thermodynamics, I can give you no hope; there is nothing for it but to collapse in deepest humiliation" [4]. An important feature of this mechanism that underlies all physical processes is illustrated by the following "thought experiment." A container is divided into two compartments, one filled with water and the other with...