Prokaryotes and the sizes of their contents

Cells are small. To see them you need a microscope, and to see their contents in detail you need an electron microscope. Objects so minute that they cannot be seen with the naked eye are - by definition - remote from everyday experience. This makes it hard to grasp the scale of cells and their contents. And without a grasp of scale it is impossible to acquire a clear mental picture of a cell.

In this chapter and the following one we shall describe large-scale models of cells that can be made from ordinary household materials. These models use the familiar to represent the unfamiliar. We urge our readers to make them. They are very simple, and entertaining to build if two or three people work together on them. Seeing and touching the models will create more vivid and memorable pictures than simply reading our instructions and comments. Building them will not reveal how cells work; we shall explore that in later chapters. But it will familiarise you with the main components of cells, and it will illustrate the relationships among these components and indicate their relative sizes. The relative sizes will prove surprising.

Before we begin on the models we must introduce two technical terms that might not be familiar to everyone. Terrestrial organisms are of two kinds: prokaryotes and eukaryotes. Prokaryotes are tiny one-celled organisms such as bacteria that do not contain a separate nucleus. "Prokaryote" is derived from Greek roots meaning "before the kernel (nucleus)". Eukaryotes are organisms consisting of one or more cells, each of which does have a separate nucleus containing the bulk of the DNA. "Eukaryote" comes from the Greek for "well-formed kernel (nucleus)". Single-celled organisms such as yeasts and amoebae are eukaryotes. So are all multicellular organisms: all fungi, all plants from mosses and seaweeds to primroses and oak trees, and all animals from sponges and worms to beetles and swallows and humans. (Most scientific terms come from Greek and

Latin, or occasionally Arabic, roots. This is because, until the early 20th century, science was the pursuit of gentlemen who were educated in the Classics, and much of our knowledge has Classical and Arabic foundations. Words that are not in common use and are employed only for special technical purposes have a great advantage: their meanings remain stable and unambiguous. For science students, the drawback of such words is that they have to be learned.)

Despite appearances, which are misleading because we can only see multicellular organisms - and not even all of those - with our unaided eyes, the world's prokaryotes greatly outnumber the eukaryotes. Also, prokaryotes are far more venerable: the earliest prokaryotes lived on Earth twice or three times as long ago as the most ancient eukaryote. Bacteria have a bad press because, for historical reasons, we associate them with infectious diseases. However, very few bacteria cause disease. The overwhelming majority are not only harmless, but in some cases essential for other forms of life. For example, if it were not for the bacteria that make atmospheric nitrogen available to plants, plants would not exist - and as a result, neither would any animals, including ourselves.

Let us return to the matter of cell size. A metre ruler is divided into a thousand parts - millimetres. Everyone knows that; we can see a metre ruler and its millimetre divisions. But try to imagine a millimetre ruler divided into a thousand parts. Each part would be a thousandth of a millimetre; that is, a millionth of a metre, or micrometre. ("Millimetre" is abbreviated to "mm". "Micrometre" is abbreviated to "^m" The Greek letter mu, is the usual way of indicating "a millionth of'.) This imaginary ruler is almost impossible to picture, but to measure cells we would need only a small portion of it. A typical prokaryote is just one or two micrometres long. Eukaryotic cells vary in size (for example, plant cells are usually bigger than animal cells), but a cell in your liver - to take an example at random - might be some fifteen or twenty micrometres across. A small eukaryotic cell is around ten times greater in linear dimensions (that is, ten times longer, wider and taller) than a prokaryotic cell. This means it is around a thousand times greater in volume. (Picture two cubes, one with one-centimetre edges and the other with ten-centimetre edges. The second cube has a thousand times greater volume than the first - one litre compared to one cubic centimetre -but the difference in linear dimensions is tenfold.) In other words, eukaryotic cells are much bigger than prokaryotic ones. They also have more complicated structures. Therefore, we are going to describe two different "household" models, one for each main type of cell. In this chapter we shall describe a matchbox-sized model for a prokaryote. In the next chapter we shall describe a cardboard carton-sized one for a eukaryotic cell.

A matchbox model of a prokaryote: the advantage of being small

An ordinary matchbox measures roughly 2 inches by 1 inch by 1 inch (5 cm x 2.5 cm x 2.5 cm). Prokaryotic cells are not exactly rectangular, as matchboxes usually are, but they have similar proportions. To make a matchbox model of a prokaryote, let one inch (2.5 centimetres) of matchbox represent one micrometre of cell. So the matchbox corresponds to a prokaryote of "typical" size, 2 ^m x 1 ^m x 1 ^m.

We have magnified the cell to the size of a matchbox, so we must magnify its contents in proportion. First, we need to consider the DNA. Prokaryotic DNA is circular; we can represent it by cutting a piece of thread of suitable length and knotting the ends together. A real bacterial DNA is about one third to one half of a millimetre long (300-500 ^m)1, so the matchbox model will need to contain a thread that is between 25 and 42 feet (7.7 and 13 metres) long. When you cut a thread of this length and knot the ends together, the result is a tangled circle. When you push this circle into the matchbox it becomes even more tangled. Unless you have used very fine thread the circle will have overfilled the matchbox - a problem, since we have many more items to add to the model; DNA is only one of the cell's many constituents.

Although the model is far from complete it has already demonstrated some important points. First, it has shown that DNA is an extremely long molecule, hundreds of times longer than the cell that contains it. Second, DNA must also be a very thin molecule, or it would not fit into the cell however hard you pushed it. Third, when DNA is packed into a cell, it is twisted and folded into a shape undreamed of by the most mischievous kitten among knitting wool. Making the matchbox-and-thread model brings these points home convincingly.

Cell functions are not topics for this chapter, but most people know that DNA is the material of the genes. A gene is a segment of DNA. In the matchbox model, an average-sized gene is represented by about one centimetre of the 'DNA' thread. For the time being we shall assume that each gene codes for one cell protein. (This assumption is not exactly true but it will suffice until chapter 11.) To make the protein corresponding to one gene, i.e. the protein encoded in that gene, the cell needs the right equipment. This equipment includes various kinds of RNA; molecules

1 Bacterial DNA is roughly one million bases long, a "base" being a single unit (letter) of the coded information that the molecule contains. In the commonest double-helical form of DNA, one base occupies a length of 0.34 nanometers, a nanometre being a thousand-millionth of a metre (i.e. a thousandth of a micrometre or a millionth of a millimetre). One million bases at 0.34 nanometres per base comes to 0.34 millimetres (340 micrometres) in total.

similar to DNA but much shorter and less stable. One sort of RNA, known as "messenger", is a copy or imprint of a gene or a small group of genes.

Think of the DNA as a library of master documents, none of which can be removed from the library but any of which can be photocopied. Each document is a gene, a coded instruction for making a particular protein. The messenger RNA molecules are the photocopies; they can be taken out of the library. Each messenger photocopy is fed into the ribosomes, remarkable machines that scan the photocopied document, translate its instructions and make the protein encoded in the gene. Thanks to this system, the instructions in a gene can be used for manufacturing thousands of copies of the same protein. Proteins are responsible for all the structures and activities of the cell: holding the cell together, sensing and responding to the environment, taking in nutrients and metabolising them, controlling the energy supply, manufacturing other cell constituents, copying DNA, making RNA, using ribosomes, and so on. The proteins, not the DNA that codes for them, are largely responsible for the "living state".

RNA molecules, ribosomes and proteins all need to be represented in the matchbox model. At any moment a prokaryote contains roughly as much RNA as it does DNA. So cut another ten metres or so of thread and put that into the matchbox. (For authenticity, you should snip this second piece of thread into 1-10 centimetre segments. This would represent the RNA molecules more realistically. However, repeated snipping is tedious and adds little to the point of the exercise.) A rounded teaspoonful of lentils represents the ribosomes. The cell's proteins can be represented by a rounded teaspoonful of sugar. If a prokaryote is magnified to the size of a matchbox, each protein molecule it contains is, on average, about the size of a sugar grain, and each ribosome is about the size of a lentil.

These proportions might seem hard to believe. Many biologists can remember feeling incredulous about them on first encounter. (One of the present authors recalls checking the calculations six times, sure there must be a mistake somewhere.) The circular 'DNA' thread in the matchbox model represents about 1000 genes, so the average gene corresponds to roughly one centimetre of thread. On the same scale, the protein encoded by the gene corresponds to a grain of sugar. Gene is to protein as a centimetre of thread is to a sugar grain. Yet that single grain of sugar, the protein molecule, is the whole point of the gene, because the proteins are responsible for virtually all the cell's structures and activities.

We have dealt now with most of the contents of a prokaryote: the huge circular DNA molecule, the many shorter RNA molecules copied from the DNA, the proteins that are necessary for the cell's structure and all its activities, and the ribosomes for making the proteins. There are tiny nutrient molecules as well, and the cell could not function without them, but in toto they occupy relatively little space. Some prokaryotes contain storage granules (food reserves), so add half a dozen dried peas to the matchbox to represent these. And of course there is water - about 20 ml in the matchbox model - but we would not recommend actually adding it; the results would be messy. Just imagine that the remaining space in the model is water not air, and ask yourself how the matchbox can accommodate 20 ml of it, considering the space occupied by the other contents.

Then close the box.

A question will strike you immediately. Why is everything packed so tightly? Why is the cell not bigger? If you have so much luggage to pack why not use a suitcase? The accepted answer is as follows. If you reproduce in the simplest possible way, that is, by duplicating all your contents and then splitting into two pieces so that one copy of everything goes into each half, it is an advantage to be small. The smaller you are, the less of you there is to duplicate, so the less time and energy it takes. Therefore, by being as small as an organism can be, prokaryotes maximise their reproductive rates. So their populations grow at the greatest possible speed - until they run out of nutrients.

Producing the maximum number of descendants is a basic biological "drive". The aim is the long-term survival of the genes. Explosive population growth helps to ensure this outcome. Because they are as small as possible and therefore reproduce as quickly as possible, bacteria can transmit their genes to large populations of descendants in the shortest possible time. At maximum growth rate, a bacterial cell may divide every twenty minutes. If there is one cell at time zero, there are two after twenty minutes, four after forty minutes, eight after an hour, sixty-four after two hours, and so on. Given an inexhaustible nutrient supply, there would be about 4,722,366,483,000,000,000,000 cells, 14,000 tonnes of solid bacteria, after a day's growth from a single cell. Of course the nutrient supply would run out long before that number was reached, but bacteria do proliferate very quickly under optimal conditions. It gives their genes the best long-term chance of survival.

The prokaryotic cell surface: the drawback of being small

The matchbox model has served its two main purposes: (1) to give a clear impression of the relative sizes of cell, DNA molecule, protein molecules and ribosomes, and (2) to show that a prokaryotic cell is about as small as it can possibly be - it is very tightly packed. The model has also led to a discussion of the relationship between cell size, population growth, and the biological imperative to transmit genes to future generations. (More about this "drive" later.) Like any model, however, it has limitations. We have mentioned two of these already: prokaryotes do not have sharp corners and edges like a matchbox; and the model is static - it does not represent any of the myriad activities, including reproduction, in which a cell engages. There is another limitation as well, rather an important one: the model misleads us about the nature of the cell surface.

Fig. 2-1: A bacterial cell surface.

The cardboard of the box can be taken to represent the tough protective coat surrounding most prokaryotes, the cell wall. Inside the cell wall, however, there is a very thin continuous coat, the cell membrane2, which in

2 Some prokaryotes (Gram negative bacteria, for instance) have an extra membrane outside the cell wall, but we shall not develop this point here.

our matchbox model would have to be represented by an unbroken seal of polythene or cellophane about a quarter of a millimetre thick. Despite its unimpressive appearance, the membrane is one of the most active and versatile parts of the cell. It jobs include:-

• Separating the cell interior from the outside world, preventing inadvertent mixing.

• Controlling the flow of materials into and out of the cell.

• Enabling items of food in the outside world to be digested, and importing the products of digestion to the cell.

• Detecting stimuli (the whereabouts of food, the location of danger, etc) and initiating appropriate responses.

• Playing a central role in making energy available to the cell. In some prokaryotes, it traps energy from the outside world and changes this energy to a form that the cell can use. (Cyanobacteria, for example, trap the energy of sunlight.)

• Housing the equipment for manufacturing many of the cell's constituents, including the external wall.

• Initiating and controlling the duplication of the DNA - the essential step before cell division (reproduction).

The first two of these functions are clearly linked. The surface membrane must be a barrier but not an impermeable one; it has to be selective. It must enhance the entry of materials that the cell needs and the exit of waste products, but it must be a barrier to everything else. Designing a structure with such exacting properties would be an engineer's nightmare, particularly if the barrier had to be no more than ten nanometres (one hundred-millionth of a metre) thick, the usual thickness of biological membranes. Yet life on Earth produced this structure thousands of millions of years ago.

Because of the membrane's remarkable range of functions, being small is in some ways a disadvantage for prokaryotes. The smaller the cell, the smaller the area of the cell membrane. The smaller the membrane area, the less equipment can be fitted into it. The fewer the pieces of equipment, the more limited the range of membrane functions. Thus, the number of different materials that can be exchanged across the cell surface, the variety of cell components that can be manufactured, the range of stimuli to which the cell can respond, and so on, are all limited because prokaryotes are as small as they can be. In other words, being small restricts the adaptability3 of a prokaryote to changing conditions. It cramps the cell's lifestyle.

3 "Adaptability" is an ambiguous word. It is used in different senses in different biological contexts, particularly when evolution is being discussed. Here we use it to mean the ability to survive changes in environmental conditions.

Prokaryotes have evolved remarkable ways of circumventing these limitations. Some bacteria change when the going gets tough into a very durable quiescent form, an endospore - a sort of suspended animation. They come back to life when conditions improve. Some can swim away from danger to a more comfortable environment. Some have genes that switch on

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Fig. 2-2: Variety of shapes of cells belonging to just one group of bacteria (cocci).

and off in response to changing conditions, increasing adaptability. Many bacteria can exchange pieces of DNA with other kinds of bacteria, passing genes to quite different organisms. This is how antibiotic resistance has spread, creating a significant worry for the medical profession. Also, bacteria work in teams. In their natural habitats, different types of prokaryotes can assemble into mixed groups and pool their resources and capabilities for the advantage of all. These groups often have beautiful geometries.

To witness such devices is to realise that our wonder at Nature need not -indeed, should not - be restricted to the everyday macroscopic world of oaks, primroses and beetles. Nature under the microscope is wonderful and enchanting too. This is a case where the ability to explain what we observe is a major ingredient of our enchantment. Knowledge does not merely enhance pleasure; sometimes, as when we contemplate these startling assemblies of bacteria, it is essential for it.

Nevertheless, despite the remarkable devices by which bacteria cope with difficult circumstances, the limitation imposed by the small cell membrane area is intractable. Being small enables cells to reproduce at maximum speed. But it imposes severe restrictions on their individual ability to adapt.

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