The Sodium Pump and Its Rivals: An Example of Conflict Resolution in Science

THE SODIUM PUMP AND ITS RIVALS: AN EXAMPLE OF CONFLICT RESOLUTION IN SCIENCE JOSEPH D. ROBINSON* Ling and Negendank, in a recent Letter to the Editor [1], consider two conflicting scientific models, the sodium-pump and the associationinduction hypotheses, in the light of past scientific conflicts, citing Lavoisier, Darwin, and Planck. Their letter reflects an interpretation of the history of science that is, I believe, mistaken both in its general formulation and in its applicability to the pump controversy. Because the resolution of conflicts is centrally pertinent to the practice and progress of science, it seems worthwhile to recapitulate briefly the course of development and criticism of the sodium-pump proposal and then to compare the dispute to an episode in the history of science that Ling and Negendank refer to, namely, the conflict between the phlogiston and the oxygen theories of combustion. Such a comparison not only reveals issues vital to the course of experimental studies on these topics but also provides illustrative lessons in the effective conduct of such disputes. Recognition of the asymmetric distribution of cations between the cell interior and its environment early inspired two classes of models: the fixed-charge hypotheses in which this asymmetry resulted from selective adsorption in the cytoplasm of the cell, and membrane-pump hypotheses in which it resulted from pumps in the membrane that selectively transported cations into or out of the cell (citations to original reports for these and subsequent issues may be found in references [2-9]). Neither class of models is inherently implausible, or exclusive, and the subsequent evolution of the field has not followed the refutation of one point of view or the elaboration of "crucial" experiments. Instead, the The author thanks his colleagues in the history of science discussion group, State University of New York Upstate Medical Center, for their attention to his recapitulation of the Priestley-Lavoisier conflict, and the National Institutes of Health for current support of research on membrane pumps: grants NS-05430, NS-12193, and GM-25033. ?Department of Pharmacology, State University of New York, Upstate Medical Center, Syracuse, New York 13210.© 1982 by The University of Chicago. All rights reserved. 003 1 -5982/82/2503-0274$0 1 .00 486 I Joseph D. Robinson ¦ Sodium Pump membrane-pump hypotheses have developed with so little concern for the alternative fixed-charge hypotheses that, as Catchpole notes [10], the alternative is generally not even cited. Why this should be so can perhaps be appreciated by a brief summary of some major events in the elaboration of the sodium-pump hypothesis, as contrasted to that of the rival association-induction hypothesis. The sodium pump, in its early formulations, provided a ready explanation for the asymmetric distribution of sodium and potassium, the fluxes of these cations and their relationship to cell metabolic rates, and the apparent osmotic properties of cells in response to such fluxes. A major step forward was the demonstration by Schatzmann that cardiac glycosides (e.g., ouabain) specifically blocked the cation fluxes attributed to the sodium pump, so that such sensitivity became the criterion for identifying the pump fluxes. Moreover, experiments in red blood cell ghosts and squid giant axons indicated that the energy-dependent (ATP-dependent) fluxes of sodium and potassium were those sensitive to the glycosides. The crucial event for the future development of the pump hypothesis, however, was the discovery of the Na,K-ATPase by Skou, who reported in 1957 the essential properties of a membranebound enzyme whose hydrolysis of ATP was activated by sodium and potassium. Post and co-workers in 1960 showed similar enzymatic activity in red blood cells and provided a catalog of similarities between enzyme and pump, including comparable sensitivities to activating cations and inhibiting cardiac glycosides; soon after, Glynn and Whittam demonstrated that the "sidedness" of the enzyme paralleled that of the pump, with activation in both cases by extracellular potassium and intracellular sodium. Bonting and associates, in comprehensive surveys, showed the remarkable parallel between Na,K-ATPase activity and pump fluxes, both ranging several orders of magnitude from transport epithelia to red blood cells. Schwartz, Albers, and their co-workers demonstrated that 3H-ouabain bound to the enzyme, and further studies...