Cell: The Unit of Life

In 1665 Robert Hooke cut a wafer-thin slice of cork, put it under a microscope he had built himself, and saw a honeycomb of tiny empty boxes. He called them cells. What he was actually looking at were only the dead walls left behind after the living contents had disappeared, so the first cell anyone ever saw was not alive. A few years later Anton van Leeuwenhoek, using better lenses, became the first person to see and describe a living cell. For nearly two centuries these stayed as observations and nothing more.

The theory came in two steps. Matthias Schleiden, a botanist, examined a very large number of plants and concluded that all plants are made of cells. Theodore Schwann, a zoologist, studied animal tissues, noticed that animal cells are bounded by a thin outer layer instead of a wall, and proposed that the bodies of animals and plants are made of cells and the products of cells. Put together, this became the statement that all living organisms are composed of cells and products of cells. But neither man could explain where a brand new cell comes from. That gap was filled by Rudolf Virchow, who argued that every cell arises from a pre-existing cell by division, summed up in the Latin phrase Omnis cellula-e cellula. So the modern cell theory has three parts: all organisms are made of one or more cells, the cell is the basic structural and functional unit of life, and all cells come from pre-existing cells.

Now the exceptions, because the theory is a very good generalisation and not a law. First, viruses are not made of cells at all. A virus is a nucleic acid inside a protein coat with no protoplasm and no machinery of its own, and it can multiply only inside a living host cell. Viroids, which are just naked RNA, and prions, which are infectious proteins, are even further from being cells. Second, some organisms are coenocytic, meaning a single continuous mass of cytoplasm holds many nuclei with no cross walls dividing it into separate cells. Rhizopus, a common bread mould, and the alga Vaucheria are the usual examples, and in them the tidy idea of one cell with one nucleus simply does not apply. Third, the very first cell on earth could not have arisen from a pre-existing cell, so the third part of the theory cannot cover the origin of life itself. Fourth, mature mammalian red blood cells and the mature sieve tube elements of the phloem throw out their nucleus and yet continue to work as living parts of the body.

Cells also vary enormously in size and shape. Mycoplasma, the smallest cells known, are only about three-tenths of a micrometre long, while typical bacteria are three to five micrometres. A human red blood cell is about seven micrometres across, nerve cells are among the longest cells in the body, and the largest isolated single cell is the egg of an ostrich. Shape follows the job: red blood cells are biconcave discs so gases diffuse in and out quickly, columnar epithelial cells of the gut are tall and packed side by side for absorption, and a nerve cell is drawn out into a long thread because its job is to carry a signal from one place to a distant one.

Prokaryotic cells are found in bacteria, in blue-green algae, which are also called cyanobacteria, in mycoplasma and in PPLO. They are generally smaller than eukaryotic cells and multiply much faster. Bacteria come in four basic shapes that are worth learning by name: bacillus is rod shaped, coccus is spherical, vibrio is comma shaped and spirillum is spiral. The defining feature is that there is no membrane-bound nucleus and no membrane-bound organelle. The genetic material is a single large circular DNA molecule that is not enclosed by any membrane and carries no histone proteins; the region where it lies is called the nucleoid. In addition many bacteria carry plasmids, which are small circular pieces of DNA sitting outside the main genome. Plasmids often carry useful traits such as resistance to an antibiotic, and because they are small and easy to move, they are the workhorses of genetic engineering.

Most prokaryotes are wrapped in a three-layered cell envelope. The outermost layer is the glycocalyx, a sticky coat that may be a loose sheath called a slime layer or a thick, tough coat called a capsule. Below it lies the cell wall, which gives the cell its shape and stops it from bursting when water rushes in. Innermost is the plasma membrane, which is selectively permeable and looks structurally very similar to the plasma membrane of a eukaryotic cell. Bacteria are commonly sorted by the way they respond to a staining procedure called Gram staining: those that hold on to the stain are Gram positive and those that do not are Gram negative. The difference comes from the way the wall is built, and it matters in medicine because it helps decide which antibiotic is likely to work.

Because there are no organelles, the plasma membrane doubles up as a work surface. At certain places it folds inward into the cell and forms a structure called the mesosome, made of vesicles, tubules and flattened sacs. This folding hugely increases the membrane area and the amount of enzyme the cell can hold on it, and the mesosome is linked to cell wall formation, to replication of DNA and its distribution to daughter cells, and to respiration and secretion. In cyanobacteria there are other membranous infoldings called chromatophores, and these carry the photosynthetic pigments.

For movement, many bacteria have flagella. A bacterial flagellum is a thin, filamentous extension of the cell surface built from three parts: the filament, which is the longest portion and sticks out into the surroundings, the hook, and the basal body that anchors it. Bacteria also carry two surface structures that have nothing to do with movement, and this is a very common trap. Pili are elongated tubular structures made of a special protein, and fimbriae are small bristle-like fibres sprouting all over the surface that help the bacterium stick to rocks in flowing water or to the tissues of a host.

Prokaryotic ribosomes are of the 70S type and are made of two subunits, one of 50S and one of 30S. They are found in the cytoplasm and also attached to the plasma membrane, and they are the site of protein synthesis. Several ribosomes often line up along a single strand of messenger RNA to translate it together, and such a string is called a polysome or polyribosome. Finally, reserve material inside a prokaryote is stored in inclusion bodies, which lie free in the cytoplasm and are not bounded by any membrane. Phosphate granules, cyanophycean granules and glycogen granules are of this type. Gas vacuoles, found in blue-green, purple and green photosynthetic bacteria, are another kind of inclusion and give the cell buoyancy so it floats where light is available.

The accepted picture of the plasma membrane is the fluid mosaic model, put forward by Singer and Nicolson in 1972. The framework of the membrane is a double layer of lipids, mostly phosphoglycerides. Each lipid molecule has a water-loving polar head and two water-hating non-polar tails. When such molecules are surrounded by water on both sides, they line up on their own so that the heads face the watery fluid outside and inside the cell, and the tails turn inward and face each other. This is why a membrane forms spontaneously and why it seals itself if it is punctured.

Sitting in this lipid sheet are proteins, and they come in two kinds. Integral proteins are partly or completely buried in the bilayer, and it is these that usually form channels and pumps because they run right through the barrier. Peripheral proteins lie on the surface of the bilayer and can be removed without disturbing the layer itself. The word mosaic in the model refers to these protein patches scattered through a lipid background, and the word fluid refers to the fact that lipid molecules can move sideways within their own layer. That quasi-fluid nature is not a detail to be memorised and forgotten; it is what makes cell growth, the formation of junctions between neighbouring cells, secretion, endocytosis and cell division possible, because none of these could happen in a rigid sheet. The ratio of protein to lipid is not fixed. In the human red blood cell membrane roughly half the material is protein and about forty per cent is lipid, while other membranes hold quite different proportions.

The most important job of this membrane is deciding what gets in and out. Small non-polar molecules that dissolve in lipid simply diffuse across from the side where they are more concentrated to the side where they are less concentrated. This is passive transport, and the cell spends no energy on it. Water moves in the same passive way, by osmosis. Polar and water-soluble molecules, however, cannot slip through the oily core in the middle of the bilayer, so they have to be carried across by membrane proteins. Sometimes the cell needs to move a substance from where it is scarce to where it is already plentiful, which is uphill work. This is active transport, it is always carrier mediated, and it costs energy in the form of ATP. The sodium potassium pump, which pushes sodium out and potassium in against their gradients, is the standard example.

Plant cells, fungi and many algae add a non-living rigid layer outside the membrane called the cell wall. It gives the cell a definite shape, protects it from mechanical damage and infection, stops the cell from bursting when it absorbs water, and helps in cell to cell interaction. Its material varies with the group. Algal cell walls are made of cellulose, galactans and mannans along with minerals such as calcium carbonate, while the walls of other plants are made of cellulose, hemicellulose, pectins and proteins. A young plant cell first builds a primary wall, which is capable of growth; that capacity for growth gradually diminishes as the cell matures. Once growth stops, a secondary wall is laid down on the inner side, that is, on the side facing the plasma membrane, and the wall as a whole ends up thicker, not thinner. Between the walls of two neighbouring cells lies the middle lamella, a layer of calcium pectate that glues them together. The neighbours are not sealed off from one another, because fine cytoplasmic channels called plasmodesmata run through the walls and connect the living contents of adjacent cells.

Some organelles are grouped as the endomembrane system because their functions are coordinated with one another rather than because they look alike. The members are the endoplasmic reticulum, the Golgi apparatus, lysosomes and vacuoles. Mitochondria, chloroplasts and peroxisomes are deliberately left out of this group, because their work is not coordinated with the others. It helps to picture the system as a single production line: goods are made at one station, sent forward for finishing, labelled, and then despatched.

The endoplasmic reticulum is a network of tiny tubular and sheet-like membranes spread through the cytoplasm, and it divides the interior of the cell into two compartments, the space enclosed inside the membranes and the cytoplasm outside them. Where ribosomes are attached to its outer surface it looks rough under an electron microscope and is called rough endoplasmic reticulum. Rough ER is often continuous with the outer membrane of the nucleus, and it is abundant in cells that are busy making protein for export, such as the enzyme-secreting cells of the pancreas. Where there are no ribosomes it is smooth endoplasmic reticulum, and this is the main site of lipid synthesis. In animal cells the smooth ER also makes steroid hormones, which is why it is well developed in the cells of the adrenal cortex and the gonads.

Material made in the ER moves on to the Golgi apparatus, first observed by Camillo Golgi as dense bodies near the nucleus. It is built of flattened, disc-shaped sacs called cisternae, each roughly half a micrometre to one micrometre across, stacked one above the other in a parallel pile with their number varying from a few to more than twenty. The stack has two clearly different ends. The face lying closest to the endoplasmic reticulum is the cis or forming face, where new material arrives; the opposite end is the trans or maturing face, from which finished material is shipped out. The two faces are not merely at different positions, they contain different enzymes, which is why a protein is chemically altered step by step as it travels across the stack. The Golgi is therefore the main packaging organelle of the cell, sending materials in vesicles either to other parts of the cell or out of it. It is also the place where glycoproteins and glycolipids are made, and it is where lysosomes are formed.

Lysosomes are membrane-bound vesicles that bud off from the Golgi and are filled with hydrolytic enzymes, mainly lipases, proteases and carbohydrases. A point worth remembering is that these enzymes are optimally active at an acidic pH, so even if they leaked into the near-neutral cytoplasm they would work poorly. They are able to digest carbohydrates, proteins, lipids and nucleic acids, which is how the cell breaks down worn-out organelles and engulfed material. Vacuoles are membrane-bound spaces in the cytoplasm holding water, cell sap, excretory products and other substances the cell does not need in its cytoplasm. In a plant cell the vacuole is bounded by a single membrane called the tonoplast and may take up as much as ninety per cent of the volume of the cell, which is a cheap way for a plant cell to become large without building more cytoplasm. The tonoplast pumps ions into the vacuole against the concentration gradient, so the sap ends up far more concentrated than the cytoplasm, and the resulting water uptake keeps the cell firm. In Amoeba there is a contractile vacuole that helps in excretion and in getting rid of excess water, and many single-celled organisms form food vacuoles around the particles they engulf.

Mitochondria are almost invisible in an ordinary preparation unless they are specially stained, and their number in a cell depends on how much work that cell does, so a hard-working muscle or liver cell carries far more of them than a resting cell. Each is usually sausage shaped or cylindrical, with a diameter between about two-tenths and one micrometre and a length of roughly one to four micrometres. A mitochondrion is bounded by two membranes. The outer membrane is smooth and forms the continuous outer boundary of the organelle. The inner membrane is thrown into a series of infoldings called cristae that project into the interior, and this folding matters because it multiplies the surface available for the enzymes that make ATP. The two membranes create two compartments: the narrow space between them, and the matrix enclosed by the inner membrane, which is filled with a dense material. The matrix holds the enzymes of aerobic respiration, and because the ATP that powers the rest of the cell is produced here, the mitochondrion is called the power house of the cell. The matrix also contains a single circular DNA molecule, a few RNA molecules and 70S ribosomes, so a mitochondrion synthesises some of its own proteins, and it divides by fission rather than being built afresh each time.

Plastids are found in plant cells and in euglenoids. They are large enough to be seen easily under a light microscope and are classified by the pigment they carry. Chloroplasts contain chlorophyll along with carotenoid pigments and trap light energy for photosynthesis. Chromoplasts carry fat-soluble carotenoid pigments such as carotene and xanthophylls but no chlorophyll, and they give the yellow, orange and red colours of many petals and ripe fruits. Leucoplasts are colourless plastids that store food, and their three kinds are worth separating carefully: amyloplasts store starch, elaioplasts store oils and fats, and aleuroplasts store proteins.

A mesophyll cell of a leaf may contain twenty to forty chloroplasts. Each is lens shaped, oval or spherical, about five to ten micrometres long and two to four micrometres wide, and is bounded by two membranes of which the inner one is less permeable. The space enclosed by the inner membrane is the stroma. Inside the stroma lies a system of flattened membranous sacs called thylakoids, and where these are piled one on top of another like a stack of coins the pile is called a granum. Flat membranous tubules called stroma lamellae connect the thylakoids of one granum to those of another. The chlorophyll sits in the thylakoid membranes, so the light-trapping reactions of photosynthesis happen there, while the stroma holds the enzymes that build sugars, along with small double-stranded circular DNA molecules and 70S ribosomes. Because mitochondria and chloroplasts share the same set of features, a double membrane, their own circular DNA, their own 70S ribosomes and division by fission, both are described as semi-autonomous organelles.

Ribosomes, first observed by George Palade, are the odd ones out in this section because they are not bounded by any membrane at all. They are granular structures made of ribonucleic acid and proteins, and they are the actual site where proteins are assembled. Eukaryotic ribosomes floating in the cytoplasm or attached to the ER are of the 80S type, made of a 60S and a 40S subunit, while those in prokaryotes and inside mitochondria and chloroplasts are of the 70S type. The letter S stands for the Svedberg unit, which measures how fast a particle settles when spun in a centrifuge and therefore reflects both its size and its shape. That is the reason a 60S subunit joined to a 40S subunit gives 80S and not 100S, a result that looks like an arithmetic mistake until you know what S means.

The cytoplasm is not an empty bag of fluid. Running through it is an elaborate network of filamentous proteins called the cytoskeleton, made up of microtubules, microfilaments and intermediate filaments. Microtubules are hollow tubes built of the protein tubulin and microfilaments are thin threads built mainly of actin. Together this network gives the cell mechanical support, maintains its shape, and takes part in movement inside and of the cell. Unlike a bony skeleton it is not permanent: parts of it are built up and taken apart again as the cell changes shape, moves organelles about or prepares to divide.

Cilia and flagella are hair-like outgrowths of the cell membrane. Cilia are short and usually present in large numbers, and they beat back and forth like tiny oars so that either the cell moves through the fluid or the fluid is swept past a stationary cell. Flagella are fewer and much longer and are responsible for moving the cell. Both are covered by the plasma membrane, and both are built around a core of microtubules called the axoneme, which runs along the whole length. In the axoneme there are nine pairs of microtubules, called doublets, arranged around the outside, and two single microtubules lying in the centre, which is why the pattern is described as the nine plus two array. The two central tubules are joined to one another by a bridge and are enclosed by a covering called the central sheath. This sheath is connected to one microtubule of each peripheral doublet by a radial spoke, so there are nine radial spokes in all, and the peripheral doublets are also joined to each other by structures called linkers. Each cilium or flagellum grows out of a centriole-like structure at its base called the basal body.

The centrosome is an organelle that usually lies close to the nucleus in an animal cell and contains two cylindrical structures called centrioles, surrounded by a shapeless material called the pericentriolar material. The two centrioles are not parallel; they lie at right angles to one another. The internal design of a centriole is described as a cartwheel: nine evenly spaced fibrils of tubulin are arranged around the edge, and each of these fibrils is a triplet rather than a doublet. The adjacent triplets are linked to one another. The central part of the cartwheel is a proteinaceous hub, and it is joined to the peripheral triplets by radial spokes made of protein. Notice that there is no central microtubule at all, which is why the centriole pattern is written as nine plus zero. The centrioles have two important jobs: they form the basal bodies from which cilia and flagella grow, and they organise the spindle fibres that pull chromosomes apart during cell division.

The contrast between the two patterns is easy to lose, so hold it as a sentence rather than as a remembered picture. The axoneme of a cilium or flagellum has nine peripheral doublets plus two central singlets. The centriole and the basal body have nine peripheral triplets and nothing in the centre. One more distinction is worth guarding: a bacterial flagellum shares the name and the job with the eukaryotic flagellum but not the structure. The bacterial one is a filament with a hook and a basal body and contains no microtubule axoneme, while the eukaryotic one is a microtubule bundle wrapped in the plasma membrane.

The nucleus was first described by Robert Brown in 1831, and the stained material inside it was named chromatin by Flemming. In a cell that is not dividing, which is the state called interphase, the nucleus shows three things clearly: a nuclear envelope, one or more nucleoli and a mass of chromatin. The nuclear envelope is made of two membranes lying parallel to one another with a gap between them, the perinuclear space, which is roughly ten to fifty nanometres wide. This double envelope is what separates the nucleoplasm from the cytoplasm. The outer of the two membranes usually continues with the endoplasmic reticulum and carries ribosomes on its surface, so the nucleus is physically joined to the protein-making network of the cell. At many places the two membranes fuse and leave openings called nuclear pores, and these are the routes through which RNA and protein molecules pass in both directions. A nucleus with no way in or out would be useless; the pores are what let the instructions stored inside reach the machinery outside.

The nucleoplasm holds the nucleolus and the chromatin. The nucleolus is a spherical body that is not bounded by any membrane, and it is the site of active ribosomal RNA synthesis. Cells that make protein heavily have larger and more numerous nucleoli, which is a good example of structure following function. Chromatin appears as an interwoven mass of thread-like structures and is made of DNA, some RNA, basic proteins called histones and non-histone proteins. When the cell begins to divide, this loose chromatin coils and condenses into the compact bodies we call chromosomes. The number of chromosomes is fixed for a species; a human somatic cell has forty-six.

Every chromosome has a narrowed region called the primary constriction, and this is the centromere. On either side of the centromere lies a small disc-shaped structure called the kinetochore, and it is to the kinetochores that the spindle fibres attach when chromosomes are pulled to opposite poles. The centromere divides the chromosome into two arms, and its position along the length is used to sort chromosomes into four types. A metacentric chromosome has the centromere in the middle, so the two arms are practically equal. A sub-metacentric chromosome has the centromere a little away from the middle, giving one shorter arm and one longer arm. An acrocentric chromosome has the centromere very close to one end, so one arm is extremely short and the other is very long. A telocentric chromosome has the centromere right at the terminal end.

Some chromosomes carry a second narrowing at a fixed place, called a secondary constriction, and unlike the rest of the chromosome it does not take up stain. The short piece of chromosome lying beyond such a secondary constriction looks like a small separate fragment and is called the satellite. Finally, it is worth returning to a point made earlier. The nucleus is essential because it holds and protects the genetic instructions and controls the activity of the cell, and yet a few specialised cells give it up once their structure is complete: the mature red blood cells of mammals and the mature sieve tube elements of the phloem both function without a nucleus, the sieve tube being kept alive by the companion cell beside it.