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ON THE DIALECTIC BETWEEN MOLECULAR BIOLOGY AND INTEGRATIVE PHYSIOLOGY: TOWARD A NEW MEDICAL SCIENCE DAVID S. GOLDSTEIN* In medical science in general, and at the National Institutes of Health in particular, the last two decades have witnessed the remarkable ascendance of molecular biology and molecular genetics, which by now have outdistanced integrative physiology in the race for money, personnel, space, and programmatic priorities. Yet according to SirJames Black, who shared the Nobel Prize for Physiology or Medicine in 1988, the future will see "the progressive triumph of physiology over molecular biology" [I]. This essay offers a less belligerent and more philosophical view, which is that the present struggle continues an ancient dispute about what medical scientific knowledge is and about how one should go about acquiring it. The resolution will not be by victory for either side but by merging of the two disciplines into a new one. More about that later; first let us analyze the strengths and weaknesses of molecular and integrative science in explaining clinical dysfunction and disease. Linear vs. Homeostatic Perspectives Molecular medical science uses a stepwise, regressive, essentially linear approach to acquire knowledge about causes of disease. One identifies the proximate preceding step, then the next proximate step, and so on, in a seemingly never-ending quest to identify one or perhaps a few "first causes" of clinical phenomena. Suppose a disease has several "causes," and suppose that for the most common ones, feedback loops, modulators, and parallel pathways complicate the picture. Using molecular genetic approaches, the exact mutation associated with a rare inherited form of the disease could be identified. One mightjustify the search for the rare mutant gene, not only because of * Clinical Neuroscience Branch, National Institute of Neurological Disorders and Stroke, 9000 Rockville Pike, Bethesda, MD 20892-1424.© 1997 by The University of Chicago. All rights reserved. 0031-5982/97/4003-1016$01.00 Perspectives in Biology and Medicine, 40, 4 ¦ Summer 1997 | 505 the potential to identify a first cause but also because the information gained could apply later to the other more complex, more common pathways. Moreover, one might presume that, after identification of a defective gene, reversal of the steps in the discovery process might "explain" the disease. Even if all patients with a particular disease shared the same mutation , however, this would not imply that all people with the mutation would develop the disease—exactly because of the multiple feedback loops, modulators , and parallel pathways, operating at genetic, molecular, cellular, and systemic levels, that characterize living organisms. For instance, the mutation might lead to the disease only in the setting of another mutation, or dysfunction of a membrane ion channel, or deformed cell structure, or failure of an organ. The lack of a word to describe the conceptual foundation of integrative physiology has led to the proposition here of a neologism: "homeostatism ." Homeostatism uses a feedback-dependent (i.e., circular) approach to the apparent steady-states that characterize all living things. The principle underlying homeostatism is that organisms maintain their internal environment by the operation in parallel of adaptive, feedback-regulated systems. Via negative feedback regulation, comparator "homeostats," and multiple effectors, adult organisms maintain levels of monitored variables within prespecified ranges, as diagrammed in Figure 1 [2]. According to the homeostatic concept, growth, senescence, disease, and, ultimately, organismic death result from instability introduced by positive feedback loops—upward and downward spirals rather than circles—leading to new apparent steady-states. A strength of the homeostatic model lies in predicting the emergence of complex phenomena, based on processes such as compensatory activation of alternative effectors, effector sharing, and homeostat resetting. The emergent phenomena can include shifts among apparent steady-states, evocable even from near-random perturbations [3]. A weakness of the model is its essential circularity, with few or no simple causal chains or cascades, and with the possibility that diseases might arise from flaws in systems as wholes. The following tabulation contrasts the molecular and homeostatist approaches to disease causes, mechanisms, and treatments. MolecularHomeostatist RegressiveEmergent linear schemaCircular schema SerialParallel EtiologyPathogenesis Mutation model for causeEvolutionary model for cause Gene therapyOrganismic treatment Computer-aided designChess computer algorithm No "goals"Apparent purposefulness 506 David S. Goldstein ¦ Toward a New Medical Science...


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