Imperfection: Biochemical Phobias and Metabolic Ambivalence

IMPERFECTION: BIOCHEMICAL PHOBIAS AND METABOLIC AMBIVALENCE DAVID L. DRABKIN, M.D.* Ev'ry senseless thing, by nature's light, Doth preservation seek, destruction shun. SirJohn Davies (1565-1618) The Elizabethan poet thus neatly phrased his concept of biological motivation. Perhaps he has said all there is to say. The thermodynamically improbable state oflife has continued to invite speculations to explain it and to encourage the framing of hypotheses which serve to rationalize the uncertainties ofexistence or to fortify confidence in its maintenance. I have stated elsewhere that "Hegel's formula of thesis-antithesis-synthesis appears merely to outline a behavior pattern in the approach ofman to an idea" (1). The coloration of biological thought has frequently reflected the preoccupation ofthe age in which it arose. Witness the attractiveness ofmechanical analogues or models—the symbolism ofthe heat engine or, later, of the storage battery (cf. 2) or, more recently, of stabilization through inverse or negative feedback, as in "high-fidelity" electronic power amplifiers. In view ofthe maze ofthe living process, those concepts which appear to simplify or unify or suggest perfection of mechanism and the inviolability ofthe body image are more readily acceptable. The longevity ofideas is favored also by a baser element in intellectual makeup —complacency and resistance to change, rejection ofthe new. The concept of"homeostasis," overshadowed in recent years by Selye's concept ofthe "adaptation syndrome," has long influenced, ifnot dominated , the understanding ofthe body's ability to maintain itselfas a "self- * Professor and Chairman, Department of Biochemistry, Graduate School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. The title of this paper is derived from the subtitle of a lecture, "Newer Viewpoints in Biological Regulation," the last of a group of "Special Lectures in Biochemistry" delivered by the author at the University of London,June 27-July 2, I952· 473 centered unit" (3) in adjustment to stressful situations or forces, to which it is continually being subjected both externally and internally and which, in effect, must embarrass it, temporarily at least. The term "homeostatic maintenance" has been employed so frequently that it has assumed the character ofan axiom, a self-evident truth. To explain the familiar "constancy " ofconcentration or amount of body constituents under more or less customary strain or load (cf. 4)—such as, let us say, in the postabsorptive state—the theory ofgeneral homeostasis has embraced two really distinctive ideas: (1) "constancy" is under control or regulation by exceedingly complicated mechanisms dominated by such agencies as the sympathetic nervous system and/or the pituitary-adrenocortical axis and/or the hypothalamic-pituitary-adrenocortical axis; (2) the control is "purposive " in that a most vital activity (cf. 5, 6) ofmammalian bodies (which are supposedly those with the most advanced or perfected organization) is the construction and maintenance of a protective shell—the internal environment—which shields the body from external inclemency. To Claude Bernard, the envelope was the blood plasma. It was constructed internally and its composition maintained constant—-a view no doubt derived from his earlier great discovery of liver glycogen as the source ofblood glucose and his proposal—revolutionary for its day—that not only plants but also animal bodies can synthesize materials (cf. 1, 7). Moreover, the "constancy" of the plasma, Bernard's milieu organique int érieur, conferred "constancy" upon the body's component tissues and was the essential secret ofthe organism's self-regulated or free way oflife, independent ofthe variable milieu cosmique ambiant. The thought was conveyed most attractively, even by present-day Madison Avenue standards: "La fixité du milieu intérieur est la condition de la vie libre, indépendante " (6). The view ofthe blood plasma (or Cannon's "fluid matrix" [5]) as more than a medium oftransport, but an "integrating force"—-which curiously is itself protected against change and serves also as the protector of the tissues against change—has directed attention largely to plasma composition . This has delayed the quest for knowledge—-more difficult to secure —ofthe composition ofcells or ofthe changes which occur intracellularly, which Bernard might have called the milieu cellulaire. It has distracted attention from obvious consequences of homeostatically maintaining the concentration of plasma constituents in the absence of inflow from the 474 David L. Drabkin · Biochemical...