DEWITT STETTEN, JR. 



tory agents as may be closely associated with it in real life. 

 Whereas the determination of the equilibrium constant of an 

 enzyme-catalyzed reaction usually rests upon preliminary puri- 

 fication of the enzyme, it must be recognized that within the 

 cell within the liver within the peritoneal cavity of the intact 

 animal, most reactions of interest in metabolic studies do not 

 proceed to equilibrium. Indeed it is a characteristic of the living 

 organism that in general it operates quite remote from the equilib- 

 rium point. 



Disease, for purposes of the present argument, may be defined 

 as the manifestation of alterations in metabolic processes. In 

 some cases, such alterations are of a qualitative nature, involving 

 the appearance in the organism of compounds which are appar- 

 ently totally lacking in the normal animal. The presence of 

 the abnormal hemoglobin found in sickle-cell anemia (15) or 

 of the Bence- Jones protein of multiple myeloma (23) are ex- 

 amples of such qualitative changes. In more cases, the change 

 appears to be of a quantitative nature, involving alterations in the 

 rates of normally occurring processes. The chemical change 

 observed in such a patient is one of a deviation from normal in the 

 concentration of some blood, urine, or tissue constituent, reflect- 

 ing a change in the rate of production or of removal of some tissue 

 component. The concentration of glucose or of uric acid in the 

 blood may be elevated, the quantity of depot lipid may be in- 

 creased, or the concentration of serum albumin may be lowered. 



The first question which is presented by such a situation is 

 an analysis of the crude mechanism upon which the change in 

 concentration depends. Most of the tissue constituents of 

 interest in this regard are, in the normal subject, in a dynamic 

 steady state, subject to an elegantly balanced turnover wherein 

 the rate of generation is closely matched to the rate of destruction 

 or elimination. A rise in the quantity of such a constituent may 

 result equally readily from an increase in the synthetic rate or 

 from a decrease in the rate of destruction. Conversely, either an 

 increase in destruction or a decreased synthesis will result in a 

 fall in quantity. It is today possible to design experiments, in 



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