Cellular homeostasis and regulatory processes

The problem of control

During the previous chapters we have started to build up a picture of life at the cell level. The picture is not yet complete but it has progressed sufficiently for the reader to see a problem: how is the cell kept in order?

Within the tiny space of the cell, many different structures are tightly packed. These structures are continually being made, repaired, broken down, recycled and moved from place to place. Thousands of different types of proteins are being synthesised all the time, moved to specific destinations, used, and finally degraded. Some of these proteins are components of the many different membrane systems; some form loose fibrils in the cytoplasm, others are components of the cytoskeleton, still others are located inside the nucleus or the mitochondria or other membrane-bound compartments. Numerous metabolic processes are taking place simultaneously in all compartments of the cell, usually at dizzying speeds, each separate individual reaction requiring its own enzyme. And everything is continually in flux, from cellular water movements and membrane flow to the motor-driven activities of the cytoskeleton. Yet the cell appears to be calm and orderly. Cells can change in form and function, they can divide, they can die; but often they seem to remain essentially unchanged for long periods of time. In view of the mob of unruly components of which they are made, the potential for uncontrollable chaos, how is this apparent constancy achieved?

Modern biology's answer to this question is probably incomplete. In so far as an answer is available, we shall not be in a position to do it justice until chapter 9. We raise the question at this stage because we need to explore the idea of "internal state" before we can develop our picture of the cell further.

Homeostasis

The problem of maintaining order and apparent constancy was addressed at the whole-body level in humans and other mammals long before it was seriously considered at the cell level. The classical physiologists of the 19th and early 20th centuries discovered much about the workings of the human body. Amongst their achievements was the discovery that many of the body's measurable properties remain more or less constant even when they might be expected to change. For instance, healthy individuals maintain a steady blood pressure irrespective of whether they are lying down, standing up, walking or exercising vigorously, though the heart rate is markedly different in these four situations. The constancy of the blood pressure is explained as follows. Some major arteries contain pressure sensors. These sensors send messages along nerves to part of the brain, which then alters the heart rate and the diameters of some blood vessels. The effect is to keep the pressure within narrow limits. If the sensors detect a fall in arterial blood pressure, the heart speeds up and the vessels contract. These changes counteract the fall. If the sensors detect a rise, the heart slows down and the vessels dilate to bring the pressure back to normal. In other words, blood pressure is maintained by a feedback control system analogous to the thermostatic control of room temperature.

Control of blood pressure is just one of many examples of the feedback principle in physiology. Others include control of body water content, blood glucose concentration, the levels of oxygen and carbon dioxide in the blood stream, and body temperature. In each case the relevant parameter is maintained within narrow limits. If it climbs too high, control mechanisms reduce it. If it falls too low, control mechanisms increase it. Sometimes the adjustment is brought about by nerves that carry messages to and from the brain, as in the case of blood pressure. Sometimes it is achieved by the actions of hormones, as in the case of blood glucose level. (The best-known of these hormones, insulin, decreases the blood glucose level; a complementary hormone, glucagon, increases it.) In either case the essential principle is feedback: a sensor detects change and a control system counters it. Pondering the generality of this principle when he was an old man, the great French physiologist Claude Bernard famously remarked that "the constancy of the internal environment is a precondition of life".

The "internal environment" is the environment in which the body's cells live. Unless this environment stays nearly constant the cells will die. In the late 1920s, the American physiologist Walter Cannon invented a word to denote the constancy of the internal environment and the mechanisms responsible for maintaining it: homeostasis. Once again, the roots of the word are Greek: "homeostasis" means "as if standing still". The study of homeostatic mechanisms, the control of parameters through feedback, has become a large part of physiology, and Cannon's new word has entered the vocabulary of science.

Physiological variables do not actually stand still; they just appear to do so. For example, every litre of your arterial blood contains about a fifth of a gram of oxygen. If it contained significantly less, or significantly more, you would be seriously unwell. If you are resting rather than exerting yourself, it will take about six minutes for the mitochondria in your cells to turn that fifth of a gram of oxygen into water (remember that mitochondria do this in the process of making ATP). But in six minutes' time, and in an hour's time, and in a year's time, a litre of your arterial blood will still contain a fifth of a gram of oxygen, provided you keep breathing. Your cells will continue to use up oxygen and you will continue to breathe it in, and the level in your blood stream will stay more or less the same. When you exert yourself, running upstairs or lifting a heavy weight, your muscle cells consume oxygen more quickly. They have to make more ATP per second when they are working harder, so their oxygen demand rises. But you breathe more rapidly and deeply to compensate, so a litre of your arterial blood still contains about a fifth of a gram of oxygen. When your body's oxygen demand falls, as it does during sleep, your breathing slows down; once again, the same blood oxygen level is maintained. This is another example of homeostasis that depends on feedback.

At the start of chapter 5 we used the analogy of a small lake fed by streams and draining into a river. The water in the lake is continually changing but the level remains constant. This could serve as a metaphor for homeostasis.

Cellular homeostasis

Every cell in the human body must preserve a constant volume and water content. Many other parameters must also be kept constant: pH, sodium and calcium contents, ATP level, and so on. Too low an ATP level would be disastrous because many ATP-dependent processes would cease, including cell volume maintenance. Too high an ATP level would be just as bad; several key metabolic reactions would be switched off and some cellular structures would start to disintegrate. The same applies to other parameters that need to be kept within tight limits, and in all these respects the cell has to fend for itself. The homeostatic mechanisms of physiology take care of the body's internal environment, the world in which the cells live. But each individual cell still has to maintain the constancy of its own interior. This applies to all cells, not just those in the human body; all animal and plant cells, and all single-celled organisms, prokaryotes as well as eukaryotes. Indeed, a moment's reflection will tell you that a cell has to do an enormous number of tasks to regulate its own activity - after all, it has no other

"authority" to turn to! Numerous physical and chemical features of the interior of any cell must be kept within narrow bounds if the cell is to survive.

How is constancy within cells achieved? Several types of mechanism are involved. Three can be mentioned here, because they depend neither on changes in gene expression nor on stimuli from the environment. They depend entirely on the aspects of cell life that we have discussed so far in this book: structure, metabolism and transport.

One depends primarily on cell structure. Metabolites and the enzymes that process them might be located either in the same cell compartment so that they can interact, or in different compartments so that they are kept apart. Every step in metabolism depends on the metabolite having access to the appropriate enzyme, so this is a fairly crude but nonetheless effective way of controlling metabolic pathways - either enabling them to function or preventing them from functioning.

The second type of mechanism is inherent in metabolic pathway design. Every enzyme in a pathway contributes to the control of the pathway's overall rate. This topic has attracted the attention of mathematical biologists and a well-established body of theory has resulted, throwing light on some otherwise puzzling experimental data. Curiously, many biochemists pay scant attention to this body of theory and maintain that only certain "key" enzymes, which are subject to feedback control (e.g. by the end product of the pathway), contribute to metabolic rate regulation. "Key" enzymes probably help to determine the balance between alternative pathways, but in general they contribute no more to the rate of a particular pathway than any other enzyme in that pathway.

The third type of mechanism depends on transport rates. If nutrients and metabolites are supplied more rapidly, the rate of each metabolic pathway that uses them will increase. Slower supply rates mean slower metabolism. Not much research has been done on this aspect of cellular homeostasis, so details are lacking. But it might be unwise to underestimate its significance.

This picture of "cellular homeostasis" is of course incomplete. Changes in expression of genes, and responses to stimuli from outside, can modify the behaviour of a cell quite dramatically. We shall turn to these topics in the following three chapters.

Internal state

The cells of a multicellular organism such as a human take on a wide variety of roles and appearances. Taken together, all the primroses, beetles, and millions of other species of eukaryotes alive today present a bewildering range of cell types. In addition, there are the prokaryotes. Such is the variety of cell forms and functions that no single concrete definition or characterisation of "livingness" is possible. An acceptable cell-biological answer to "What is life?" has to transcend description; it must be abstract. Moreover, as we have seen, living cells are vastly complex, so to describe any cell fully would require an impossible amount of detail. A manageable definition or characterisation must cut through this morass of specifics to generalities; so our answer must be general as well as abstract.

We have already used a number of general terms. The phrase cell structure and organisation denotes all the membrane systems of the cell (mitochondria, lysosomes and so forth), the numerous fibres of the cytoskeleton, the ribosomes, chromsosomes, metabolons and other multi-molecular constituents, and their relative dispositions in space. Metabolism encapsulates all the anabolic and catabolic pathways in the cell. If these were written out in detail the result would resemble a street map of a large city filled with moving traffic. Transport covers a variety of mechanisms by which a cell's ingredients, from water and small metabolite molecules to objects as big as mitochondria, are moved from place to place. Only by describing the cell in terms of these generalities has it been possible to show that cell structure and organisation, metabolism and transport are interdependent. This was the conclusion of chapter 5. In the present chapter we have seen that in ways that are not yet entirely clear, this interdependence is partly responsible for the apparent stability and constancy of the cell's overall appearance and behaviour. Cellular homeostasis seems to be rooted (at least partly) in the three-way relationship among transport processes, metabolism and cell structure. We need a convenient term for this three-way relationship and the homeostatic control that it generates.

From now on we shall describe the picture of the cell encapsulated in Fig. 6-1 as the cell's internal state. "Internal state" denotes the quantities of all the cell's ingredients at a particular moment, their organisation in space, the sum total of the metabolic events taking place, the directions of all the transport processes and what they are transporting, and the ways in which these different features interlock. "Internal" indicates the overall situation within one cell, not what might be taking place outside it or in other cells. "State" is fairly non-committal, but connotes a definable, reasonably stable situation. When we use the expression "internal state", think of the following diagram, but bear in mind that each apex of the triangle hides a huge wealth of descriptive detail.

Fig. 6-1: the internal state of a cell.

"Internal state" is a summary description of a cell at a particular moment. In principle, it can change from one moment to the next. In practice, the internal states of most cells remain approximately constant for extended periods. However, "at a particular moment" should be regarded as part of the definition. The reason for this will become clear in the following three chapters.

The concept of internal state, which often appears to "stand still" but never does, is an important part of the answer to "What is life?" But it is not the whole answer. This is clear from the fact that we have not yet covered some of the traditional properties of organisms (response to stimuli and growth) and we have said little or nothing about reproduction or DNA or gene expression. We could not seriously tackle these aspects of biology before establishing the concept of internal state. Now that we have defined this concept, we are in a position to address them.

Before we do so, we shall look briefly beyond the cell and the single organism to the ecosystem. Does the concept of homeostasis that we have introduced in this chapter have any relevance in ecology?

"Homeostasis" in ecosystems?

In chapter 4 we suggested that the ideas of metabolism could be extrapolated from the individual cell or organism to a whole ecosystem. Energy and materials are passed in sequence between the component organisms of the ecosystem and the inorganic parts of the environment (air and soil); there is efficient recycling. This is a well-established aspect of ecology. However, whether the idea of homeostasis can be extrapolated to ecosystems is more controversial.

The population of any organism depends on the populations of other organisms in the ecosystem, particularly those that it eats (prey) and those that eat it (predators). Populations of different species are therefore interrelated. They also depend on environmental factors such as temperature and sunlight. Because of these connections, ecosystems behave as though they had internal control mechanisms: change one population level or relevant physical parameter, and the rest of the ecosystem will respond (within limits) so as to resist the change and restore the status quo. However, nothing obviously analogous to the feedback control processes in physiological homeostasis can be found at the ecological level, so to use the word "homeostasis" in this context seems dubious.

Many proponents of the "Gaia Hypothesis" think otherwise. Strictly speaking, the Gaia Hypothesis merely holds that life affects the non-living environment, just as the environment affects life. Computer models such as "Daisyworld" illustrate the idea. Briefly: imagine the surface of a planet heated by a sun and populated solely by black and white daisies. Suppose black daisies grow faster at lower temperatures and white ones at higher temperatures. Black daisies absorb solar radiation and heat up the planetary surface; white ones reflect radiation so the surface cools down. Left to its own devices, this planet will settle down to a balanced population of black and white daisies maintaining a steady surface temperature. This is an interesting observation, and more complicated computer simulations have added to the interest, but it is stretching things to call such phenomena "homeostasis". We can accept "Daisyworld" as a simplified analogue of terrestrial processes without claiming that the whole biosphere is a giant ecosystem behaving homeostatically.

This topic is of general interest, not least because of the likelihood that contemporary human activity is radically changing the Earth and its biology. It cannot be dismissed out of hand. However, because our focus at present is on cells rather than ecosystems and global ecology, we shall not discuss the "Gaia Hypothesis" further until later in the book.

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