In chapter 4 we introduced metabolism, the chains of chemical reactions that take place inside living cells. We emphasised the close reciprocal dependence between metabolism and cell structure. Now we turn to another major aspect of cell activity: transport. How are a cell's ingredients imported, exported and moved from place to place, and how are its internal structures kept in position? And how do cells move?
The contents of a eukaryotic cell range from the tiny molecules of metabolism to large internal membrane structures. A protein molecule is around ten times longer than a metabolite molecule. A molecule of RNA is hundreds of times longer than a protein. A mitochondrion is three or four times longer still, and a great deal fatter than an RNA molecule. Cargoes of such widely different sizes are unlikely to be moved efficiently by a single mode of transport. Therefore, the cell has a variety of transport mechanisms.
The main ingredient of a cell is water. An average-sized human cell contains up to 1,000,000,000,000,000 (i.e. 1015) water molecules. Picture a small lake fed by fast-flowing streams and drained by a large river; the level of water in the lake remains practically constant, and underwater currents flow, but no individual water molecule stays in the lake for long. The flux of water in a cell behaves similarly; water enters and leaves all the time and currents flow, but the amount inside the cell scarcely changes. But in a cell, unlike a lake, the "feeder streams" and "outflows" are dispersed all over the surface. Water flows continually in both directions across almost the whole of the cell membrane. Similarly, it enters and leaves each of the membranous inclusions - nucleus, mitochondria, lysosomes and so on.
Within the cytoplasm (the part of the cell outside the nucleus), water flows first one way and then another, or round in circles. These movements are generated in various ways: by activities of the cytoskeleton, transport of metabolites across membranes, and metabolic production and utilisation of water. (Remember that water is a product of catabolism9).
In chapter 4, we saw that metabolic pathways are efficient because the enzymes are fixed in ordered sequences on membranes and metabolons. Their efficiency is further enhanced by the flow of water inside the cell, which continuously feeds raw materials to the enzymes and removes the products. (Most nutrients and metabolic intermediates are soluble in water.) The principle is familiar to chemical engineers: making the reactants flow over a catalytic bed ensures that the product is made quickly and in high yield. Living cells discovered how to put this principle into practice more than a thousand million years before chemical engineers existed.
The cytoplasm is not a simple liquid, even if we discount the cytoskeleton and all the internal membrane structures. If - to revert to the box model of chapter 3 - the half-kilo of salt representing the cell's proteins had been mixed with the other solid ingredients and the appropriate volume of water (5 litres), a runny paste would have resulted. Salt is not protein but the effect is similar. Proteins are sticky molecules; they adsorb water and they adhere to each other. So the cytoplasm, minus membranes and cytoskeleton, can be pictured as a runny paste. Examined under a highvoltage electron microscope it is a loose network of thin strands, mainly water-saturated proteins. However, cytoplasm is not a stable gel like a table jelly. The strands are continually breaking and reforming; those in a table jelly are much less labile.
Water, and the small metabolite molecules dissolved in it, flow through the cytoplasm fairly easily and quickly. Bigger molecules are a different matter. They repeatedly become entangled in the network, and however quickly the strands of the network break and reform, this slows their movement. For protein and RNA molecules, which tend to stick to the network and become part of it, the slowing is potentially dramatic. They could be almost immobilised unless a path could be cleared for them.
9 A simple calculation can be made, based on the amount of oxygen your body takes up per unit time while you are at rest (sitting in a chair reading this book, for example). If we assume that nearly all the oxygen you breathe in is converted to water by catabolism in the mitochondria; your body contains ten million million cells; and an average cell contains a hundred mitochondria... then ten thousand water molecules are produced in each mitochondrion every second. If you exert yourself, then you take in oxygen more rapidly and the rate of water production increases.
Many proteins, and probably messenger RNAs, are targeted for specific destinations. A protein might be destined to remain in the cytoplasm, or to become part of a mitochondrial or lysosomal membrane, or to take up residence in the watery space inside a mitochondrion or lysosome. It might be dispatched to the cell surface or to the nucleus. It might be exported from the cell into the outside world. The cell has to ensure that the right proteins go to the right destinations. In principle, a newly-made protein could wander around the cell at random more or less indefinitely and then bind anywhere; so how is this avoided? The cell uses its proteasomes (see chapter 3) to hoover away proteins that "hang around" for more than an hour after synthesis and fail to find their destinations. This would be fatally wasteful unless there were efficient, protective cytoplasmic transport processes for large molecules.
In many instances, one part of protein molecule functions as a "travel ticket", which is recognised by a "ticket inspector" at the target site but is not valid for other destinations. This ensures that the protein stops at its ordained destination, but does not explain how it travels there. The cytoplasmic transport processes for proteins and RNAs are certainly efficient, but the mechanisms are not clear and the subject is a matter of controversy. In some cases, movements of the cytoskeleton might drag a protein along (see below). In other cases a big molecule might be passed from one strand of network to the next in a series of little jumps, perhaps with an energy-requiring (A TP-dependent) "push" to start it at source. In still other cases, big molecules might become attached to membranes and carried along by membrane flow (again, see below). And there might be other mechanisms of which we are currently ignorant.
Among some biologists, the belief persists that proteins travel in the cytoplasm by diffusion. This idea is superficially attractive because diffusion is a simple physical process, the result of random thermal motion of molecules, and requires no specially evolved apparatus. However, random molecular saccades do not provide a plausible basis for specifically directed movement over cellular distances, particularly in an environment where random motion would be seriously retarded by the cytoplasmic network.
Molecules that are insoluble in water present different problems. They cannot move by exploiting water flow in the cell. One way of transporting water-insoluble molecules is to "dissolve" them in the endoplasmic reticulum (membranes are greasy rather than watery, so they are friendly environments for water-insoluble molecules). They flow slowly along the planes of this membrane system to reach the cell surface, the Golgi complex, the lysosomes or other destination. Membranes flow rather as a slick of oil flows over water; slow movement along a plane. Just as an oil slick flows when oil is added to one side, so a membrane flows when new material is added by anabolic processes. And just as an oil-soluble substance added to the puddle will be borne across the surface in the flow of oil, so a water-insoluble molecule in a cell is borne along by the flowing membrane. Some water-insoluble molecules, however, travel by a different method. They bind to a protein that is targeted to the appropriate destination. This enables them to cross the cytoplasm under protection, much as a traveller might cross the desert by attaching himself to a camel train.
Membranes therefore act as transport routes for some water-insoluble materials. But they are barriers for water-soluble ones; the first job of the surface membrane is to stop the inside of the cell mixing with the environment. To move, say, a glucose molecule into the cell from the outside, a special piece of equipment is incorporated into the cell membrane. Many protein components of membranes are just such pieces of equipment;
devices for transporting or pumping10 particular water-soluble molecules from one side to the other. Let us sum up so far.
Transport and the cytoskeleton
The fine structure of the cytoplasm hinders the movement of large molecules such as proteins, so bigger objects such as lysosomes and mitochondria must be more or less immobile. Indeed they are, unless the cytoskeleton lends a hand.
A cytoskeletal fibre is built like a popper-bead necklace but it is more rigid. The "beads" are special sorts of protein molecule designed to fit together to form "necklaces".
The fibre can be lengthened by adding more "beads" and shortened by removing them. The lengthening (assembly) process costs energy (ATP). If beads are added at one end and simultaneously removed at the other end then the whole fibre appears to move. (Try it with a popper-bead necklace.) If the growing end of the fibre is attached to the cell membrane, the entire cell is moved as a result: the extending fibres push out the membrane, rather as you might push out the finger of a rubber glove, and the cell contents follow. Amoebae travel by this method; so do some cells in your body. If an internal membrane structure such as a mitochondrion is caught among assembling/disassembling fibres, it will be pushed from one place to another despite the resistance of the cytoplasmic gel. Perhaps such processes also move certain types of protein and RNA molecules around inside the cell.
10 In some cases the equipment for transporting a water-soluble molecule across a membrane requires energy, supplied directly or indirectly by ATP. An energy-requiring membrane transport machine is commonly called a "pump".
However, the assembly and disassembly of cytoskeletal fibres do not normally move large intracellular objects such as mitochondria. A more usual method involves motors associated with the cytoskeleton. A motor is an ATP-fuelled molecule that runs along the fibre and is attached to the object to be transported. The system is rather like a goods train on a monorail. Remarkable distances can be travelled by this mechanism. For example, neurotransmitters (chemicals that are released from the end of a nerve cell when an electrical impulse arrives) are packaged in tiny membrane-bound vesicles. These vesicles are made in the body of the nerve
cell and transported to the end of that cell, which might be surprisingly far away. The muscles that make your toes move are in the lower part of your leg. The nerves that control these muscles have their cell bodies in your spine, so the neurotransmitter vesicles have to be carried all the way down your leg to reach the ends. (Of course they are already in place when you wiggle your toes.) The axons of these nerve cells, the parts that carry the electrical impulses, extend this entire distance. The neurotransmitter packages are carried by a motor-driven mechanism along cytoskeletal fibres the whole length of the axon.
When you wiggle your toes, the muscles in your lower leg contract and relax. Muscle contraction involves specially-adapted cytoskeletal fibres in the muscle cells. These fibres, which are arranged in parallel, slide between one another, shortening the muscle cell when they slide one way, lengthening it when they slide the other. The sliding of the fibres is another motor-driven mechanism. All animal muscles seem to work in this way: your biceps, a blowfly's flight muscles, a shark's jaw, a worm's body. The cytoskeletal fibres involved in muscle contraction are different from the ones involved in neurotransmitter transport, but the underlying principle, motors running along fibres, is the same.
Eukaryotic cell division, the basis of growth, also involves motors on cytoskeletal fibres. In this case the paired duplicate chromosomes are separated by motor-driven fibres so that each daughter cell receives an equal share. A chromosome is a single DNA molecule packaged with specialised proteins. Remember there are 46 DNA molecules and therefore 46 chromosomes in an ordinary human cell. They must all be duplicated before the cell divides so that each daughter cell still has the correct chromosome number - 46. The motor-driven fibres separate one set of 46 from the duplicate set; then the cell splits into two identical, viable halves.
There is another mechanism of cell movement, found in some prokaryotes and single-celled eukaryotes. Long extensions resembling whips (flagella) protrude from the cell, and the rhythmic beating of these generates a swimming action. This rhythmic beating is another motor-driven process. In some cases the flagella describe circular movements; bacteria invented the wheel more than a thousand million years ago! Some cells in multicellular eukaryotes have rather similar projections from their surfaces. These projections, known as cilia, are extensions of the cytoskeleton and their movements are once again motor-driven. Coordinated movements of cilia along rows or sheets of cells make the surrounding fluid move, rather than the cell itself. For instance, mucus is driven along your respiratory tract by the movements of cilia on the cells lining the tubes. This process keeps the airways free of contaminants that have become trapped in the mucus.
In summary, we can make three additions to the list of cellular transport mechanisms surveyed in the first section of this chapter:-
Transport, metabolism, structure and organisation
We have now surveyed a variety of mechanisms underpinning the fifth traditional property of organisms: movement. This is almost incidental. More significantly, our discussion leads to further insights into the nature of the living state. At the end of chapter 4 we drew attention to the interdependence between metabolism and cell structure and suggested that this was the first step towards answering the question "What is the fundamental difference between living and non-living?" We can now take a further step.
Early in the chapter we noted that transport is essential for metabolism. Clearly, if enzymes fail to reach their destinations, they cannot be incorporated into the "assembly lines" responsible for metabolic pathways. This would make the pathways non-functional; metabolism will break down. Protein transport is therefore necessary for metabolism. Moreover, metabolism depends on nutrients entering the cell and on metabolites entering compartments such as mitochondria where they are processed; so transport across membranes is essential for metabolism. The flow of water in the cytoplasm ensures that metabolic processes are efficient. In these ways, metabolism depends on transport.
On the other hand, many transport processes require energy. They would cease if the cell did not supply ATP. Metabolism (specifically, catabolism) is necessary for the supply of ATP. Moreover, the equipment required to transport materials across membranes has to be synthesised in the cell, so it depends on anabolic pathways. In short, transport depends on metabolism. We suggest that the interdependence between metabolism and transport is as profound, and as integral to understanding the living state, as the interdependence between metabolism and cell structure.
There is a similar interdependence between transport and cell structure. Membrane flow carries water-insoluble molecules towards their destinations. The cytoskeleton transports large cell components. So transport often depends on cell structures. On the other hand, the cell's orderly and efficient transport mechanisms are necessary to deliver building materials to the structures for which they are destined. They are also needed to transport these structures to sites where they are needed. Thus, cell structure and organisation depend on transport; transport depends on cell structure and organisation.
In short: metabolism, transport and cell structure and organisation all depend on one another. These reciprocal relationships are characteristic of and, we believe, fundamental to the living state. It is easier to accept this in relation to eukaryotic cells than prokaryotes; the small size of prokaryotes makes transport processes hard to study experimentally. Nevertheless the same reciprocity seems to apply in prokaryotes, though the range of actual processes involved is narrower than in eukaryotes and many mechanisms are simpler. (Prokaryotes have much less elaborate cytoskeletons, for example.)
The three-way interdependence among cell structure, metabolism and transport is part of our characterisation of the living state, but it is not the whole of it. As yet, we have mentioned genes and gene expression only incidentally, and we have made only passing references to the responses of cells to environmental stimuli. We shall start to address these topics in chapter 7; but first, it is time to review our picture of the cell to date.
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