Maintaining Constancy of the Internal Environment via Control Mechanisms

The ability of organisms to maintain themselves has, at times, led biologists to reject the quest for mechanistic explanations. The vitalist Xavier Bichat (1805) opposed mechanistic explanations of biological phenomena because organisms (1) do not always behave in the same manner and (2) maintain themselves in the face of physical processes that would seem capable of destroying them (he characterized living systems as resisting death). Claude Bernard (1865) was one mechanist who took Bichat’s contentions seriously and offered a framework for developing a mechanist answer. To account for the fact that organisms do not always respond to stimuli in the same way, he argued one must view the various mechanisms that constitute the organism as operating in what he termed the internal environment. This is the environment within the organism. Variation there would account for varied responses to external stimuli. To explain the resistance to death, he proposed that each mechanism is so designed to restore the constancy of the internal environment. Bernard, however, offered little insight into how each mechanism could operate to restore the constancy of the internal environment. Recognizing negative feedback as a design principle that enabled restoring a condition to its target state, Cannon (1929) offered several examples of how the autonomic nervous system employs negative feedback to maintain what he referred to as homeostasis. In the rest of this section, I describe two biological mechanisms in which feedback serves to maintain homeostasis, both serving to maintain an internal supply of ATP, the source of energy utilized in intracellular work.

The nineteenth century witnessed intense debates as to whether fermentation, the process of metabolizing glucose to yield alcohol and carbon dioxide, could be explained in terms of chemical reactions or required a whole living organism. This debate was largely resolved when Eduard Buchner (1897) observed the formation of carbon dioxide when he added glucose to a cell-free extract and recognized this as a sign that fermentation was occurring without living cells. Although Buchner attributed this reaction to a single enzyme he named zymase, other researchers began to seek chemical intermediates, especially three-carbon compounds. Beyond the identification of pyruvate, the search for intermediates was largely foiled by the fact that most of the actual intermediates are phosphorylated compounds. Harden and Young’s (1906) demonstration of the need to supply inorganic phosphate to sustain Buchner’s reaction was puzzling since phosphates did not seem to appear in the products. Researchers soon recognized that fermentation was a variation on glycolysis, which figures in muscle contraction. Lundsgaard’s (1930) discovery that phos- phocreatine was the immediate source of energy for muscle contraction and Lohmann’s (1929) discovery that the energy released in the oxidation of glucose was captured and stored for cell use in the phosphate bonds of adenosine triphosphate (ATP) revealed the importance of phosphory- lated compounds at the end of glycolysis. Soon after, researchers showed that the intermediates in glycolysis were themselves phosphorylated and identified them. Since then, glycolysis has been viewed as a sequence of reactions as shown vertically in the center of Figure 12.2 (Bechtel 2006). Researchers recognized points at which ATP or ADP linked to the pathway (as source or recipient of phosphate bonds), but these were viewed as side processes off the main pathway.

Often glycolysis is presented as uncontrolled: as long as glucose is available, glycolysis proceeds. In fact, however, phosphorylated compounds, especially ATP, perform important regulatory roles, as shown by the reactions indicted by dashed lines on the right in Figure 12.2. Consider the third reaction in the pathway, which adds a phosphate group to fructose-6-phosphate to yield fructose-1,6-diphosphate. While ATP is an essential metabolite in the reaction itself, as it supplies the phosphate group, it is also an inhibitor of the enzyme. The enzyme phosphofructokinase-1 is an allosteric enzyme. Its conformation changes depending on whether it is bound to AMP or APD or to ATP. When bound to AMP or ADP, it phosphorylates fructose-6-phosphate more rapidly, at the expense of breaking down ATP to yield more ADP. This generates positive feedback. ATP, however, has the opposite effect, slowing the reaction. The physiological value of this design can be easily recognized. If the cell already has an ample supply of ATP, it would be wasteful to oxidize more glucose. It would be more efficient to maintain glucose in that form or convert it to glycogen until more ATP was needed.

As with negative feedback in human-made machines, negative feedback in glycolysis involves a secondary mechanism operating on the primary mechanism—the reaction pathway from glucose to lactate or alcohol. The control system is operating on the constraints (allosteric enzymes) of the main pathway, altering their operation. The next example is a little more complex since it is designed to register a condition in an organism’s environment that is necessary before a mechanism can produce its desired effects.

The glycolytic pathway is shown in the center with metabolites designated in dark text and enzymes in italics

Figure 12.2 The glycolytic pathway is shown in the center with metabolites designated in dark text and enzymes in italics. Loops show where P;, ADP, ATP, NAD+, NADH and H20 enter or leave the pathway. Dashed arrows and edge-ended lines on the right show feedback effects on enzymes (constraints) in the pathway. On the left are idealized graphs of the oscillation of the various intermediates, with dotted arrows linking the identification of the oscillating intermediates to where they appear in the pathway.

As in the case of glycolysis, it involves a control mechanism that operates on a constraint within the system that is being regulated.

In the 1930s, biochemical geneticists working with the bacterium E. coli discovered that the concentration of enzymes required for the metabolism of sugars such as galactose were not constant but would increase dramatically over time when the preferred sugar, glucose, was not available but galactose was. This process was originally designated enzyme adaptation and was thought to result in a modification of a precursor of the enzyme galac- tosidase when galactose was available. Monod, however, established that increased enzyme activity resulted from de novo synthesis of the enzyme from DNA. That is, it was by altering gene expression that control over the mechanism metabolizing galactose was achieved. This set Jacob and Monod (1961) on the quest that resulted in the discovery of one of the best-known control mechanisms in biology—the lac operon. The lac operon regulates the expression of three enzymes required to metabolize lactose, lacZ, lacY, and lacA. The key component in the operon is an allosteric enzyme, the lac repressor, which is constitutively produced by another gene, lacI. In the default state, it binds to the operator lying just in front for the three genes and largely blocks the RNA polymerase from initiating their transcription. The mechanism allows only a small, residual synthesis of lacZ. When lactose is present, the residual lacZ catalyzes the reaction producing allolactose from lactose. Allolactose binds to the lac repressor, altering its conformation so that it can no longer bind to the operator. This then allows the RNA polymerase to accelerate transcription of the three lac genes. An additional control mechanism prevents lactose from entering the cell whenever glucose is present, preventing this mechanism from accelerating the transcription of the lac genes except when lactose metabolism would be beneficial.

In this section, I have described two biological examples in which control mechanisms function to regulate the function of biological mechanisms so that they perform as needed to maintain the overall biological system. The glycolytic example involved negative feedback, in which ATP served to inhibit an operation in which it also functions as an input, thereby keeping ATP at constant levels in a cell. The lac operon uses feedback to detect the presence of lactose and accelerate the synthesis of the relevant genes when glucose is not available. In both cases the control mechanism operates on the constraints of another mechanism, adjusting its behavior so as to produce the results needed to maintain the constancy of the internal environment of the cell.

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