First Steps The Internal Environment And Negative Feedback Mechanisms

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The indeterminacy to which Bichat and other vitalists pointed is the easier of the objections for mechanists to answer, as demonstrated by Claude Bernard (1865) half a century after Bichat. Fundamental to Bernard's conception of science was explanation in terms of deterministic causal relations; accordingly, it was critical for his attempt to develop a science of experimental medicine to counter the apparent indeterminism in the activities of living organisms that Bichat had highlighted. The key element in Bernard's response was a focus on the internal organization of living systems. He proposed that each internal part of a living organism resides in an internal environment that is distinct from the external environment in which the organism as a whole dwells. With this move he could contend that whereas the response of a part of an organism to changes in the external environment might not be regular, strict determinism could be observed in the response by a component to conditions of the internal environment. For example, decreased glucose levels in the blood would regularly produce lowered metabolic activity in somatic tissue. Reduced glucose in the food, on the other hand, would not necessarily show up in reduced metabolic activity as the organism might convert energy stored in other forms, such as fat, into glucose. These other internal activities compensated for or obscured the causal link between external factors and physiological responses of the organism.

The focus on the internal environment also provided Bernard the beginnings of a response to the claim that organisms are not mechanistic insofar as they operate to resist death. The way in which the internal environment provided a buffer between conditions in the external environment and the reactive components of the mechanism, according to Bernard, was by having individual parts of the organism each perform specific operations that served to maintain the constancy of the internal environment. They thereby ensured that other component parts of the organism encounter the conditions they need in order to perform their own operations. Thus, he says "all the vital mechanisms, however varied they may be, have only one object, that of preserving constant the conditions of life in the internal environment" (Bernard, 1878, p. 121, translated in Cannon, 1929, p. 400). Insofar as some of its mechanisms are designed to maintain a constant internal environment despite changes in the external environment, a living system can appear as an active system doing things that resist its own demise.

Bernard's insights were built upon in the early-twentieth century by physiologist Walter Cannon (1929). One of his conceptual contributions was to introduce the term homeostasis (from the Greek words for same and state) for the capacity of living systems to maintain a relatively constant internal environment. He also described a number of modes of organization through which animals are capable of maintaining homeostasis. The simplest involves storing surplus supplies in time of plenty, either by simple accumulation in selected tissues (e.g., water in muscle or skin) or by conversion to a different form (e.g., glucose into glycogen) that can be reconverted in time of need. A second means for achieving homeostasis involves altering the rate of continuous processes (e.g., changing the rate of blood flow by modifying the size of capillaries to maintain uniform temperature). Cannon determined that such control mechanisms are regulated by the autonomic nervous system.

Negative feedback is an organizational principle that is crucial to understanding how biological systems are organized to maintain themselves in the face of external challenges. It perhaps was first discovered by Ktesibios of Alexandria around 270 BCE. Ktesibios faced the challenge of ensuring a constant flow of water into a water clock so that he could measure the passage of time by the accumulation of water. To do this he used a supply tank in which he maintained water at a constant level by means of a float that rose into the supply line and cut off the flow into the tank whenever it reached the target level. As water drained out of the supply tank into the collecting tank, the float dropped, allowing more water to enter the supply tank. This was an ingenious solution to a specific problem but it was not recognized as a general design strategy that could be utilized for other problems. As a result, negative feedback had to be repeatedly rediscovered in different engineering contexts in which this form of control was ideal. For example, around 1624 Cornelis Drebbel developed a temperature regulator for furnaces, and in 1745 British blacksmith Edmund Lee developed the fantail as a feedback system to keep the windmill properly oriented (Mayr, 1970).

Famously, James Watt in 1788 rediscovered the idea of negative feedback when he designed the governor, as discussed in the previous chapter, to ensure that the steam supply in his steam engine would be appropriate to keep the various sewing machines attached to it working at a constant speed even as individual machines went on- and off-line. Watt's governor became the focus of a mathematical analysis by James Clerk Maxwell (1868) that helped to establish negative feedback as a general principle for regulating complex systems. The recognition that it could regulate biological as well as engineered systems inspired the cybernetics movement of the 1940s and 1950s. With support from the Macy Foundation, mathematician Norbert Wiener and his collaborators launched a series of twice-yearly conferences known as the Conference for Circular Causal and Feedback Mechanisms in Biological and Social Systems. After Wiener (1948) coined the term cybernetics (from the Greek word for "steersman"), it was renamed the Conference on Cybernetics and galvanized a broader movement that was interdisciplinary and bold. Early on, for example, Mexican physiologist Arturo Rosen-blueth, MIT electrical engineer Julian Bigelow, and Wiener argued that negative feedback provided a means of resuscitating such notions as purpose and teleology without invoking vitalism (Rosenblueth, Wiener, & Bigelow, 1943). Their idea was straightforward and powerful: If negative feedback enabled the system to maintain a given temperature, then one could view maintaining that temperature as the system's goal or telos.

With the development of the cybernetics movement and of control theory as a central topic in engineering, negative feedback finally came to be viewed as a general design principle. Although enriched by a variety of tools, such as the use of off-line emulators and filtering techniques (Grush, 2004), negative feedback remains at the center of the modern field of control theory. It is also recognized as a general principle in the organization of biological systems that need to regulate themselves. A wide range of chemical reactions occur in even the simplest cells. If these were allowed to run unchecked, the cell would rapidly exhaust its supply of resources. Feedback loops provide a way of ensuring that critical processes, such as the consumption of nutrients to generate ATP, occur only when they are required. Figure 6.2 illustrates negative feedback at the junction between glycolysis and the citric acid cycle (shown in Figure 6.3), which is the chief pathway for oxidizing foodstuffs to produce ATP in most cells. There are pathways leading from nearly every metabolite found in the cell to the citric acid cycle; if these pathways functioned unchecked, all available metabolites would soon be oxidized. The negative feedback loop slows the generation of pyruvate from phosphoenolpyruvate (coupled with the synthesis of ATP) when there is already a plentiful supply of acetyl-CoA waiting to enter the citric acid cycle. When this happens the glycolysis pathway shown in Figure 6.1 above also slows due to the lack of available NAD+, and glucose is preserved until it is needed.

Phosphoenolpyruvate 2ADP

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