Cell Cycle and Cell Division

A cell does not divide the moment it is born. It first grows, copies its DNA, makes the proteins the coming division will need, and only then splits. This ordered sequence of events, ending with one cell becoming two, is called the cell cycle. It is described as a cycle and not a straight line because the two daughter cells that come out at the end can enter the same sequence again.

The cycle has two basic phases. Interphase is the long preparatory stretch between one division and the next. M phase, or the mitotic phase, is the short stretch in which the nucleus and then the cytoplasm actually divide. Interphase is often called the resting phase, and that name is misleading, because nothing rests. The cell is making proteins, building organelles, growing in size and duplicating its entire genome. It is called resting only because the chromosomes are not visible as separate bodies and the cell looks quiet under a microscope.

How long does one cycle take? In human cells growing in culture, one full cycle takes roughly 24 hours, and the division itself takes only about an hour of that. Interphase therefore occupies more than 95 per cent of the total time. Yeast is far quicker and can finish an entire cycle in about 90 minutes. So the timing is not fixed for all living things; it depends on the organism and on the type of cell.

M phase itself has two separate jobs, and it helps to keep them apart in your head. Karyokinesis is the division of the nucleus, and it is what the four stages of mitosis describe. Cytokinesis is the division of the cytoplasm, which normally follows karyokinesis and finally gives two separate cells. The two usually go together, but not always. If karyokinesis happens repeatedly without cytokinesis, the result is one large cell carrying many nuclei, called a syncytium. The liquid endosperm of a coconut is the familiar example: it is a mass of cytoplasm with many free nuclei in it.

One more distinction is easy to get wrong. Mitosis is usually restricted to diploid cells, and in animals it is normally the diploid somatic cells that divide this way. But usually is not always. Plants show mitotic divisions in both haploid and diploid cells, and haploid cells also divide by mitosis in some lower plants and in some social insects, so the exception turns up on the animal side too. The flat statement that mitosis happens only in diploid cells is therefore a half-truth. It is safer, and always correct, to say that mitosis leaves the chromosome number of the parent cell unchanged, whatever that number happened to be.

Interphase is split into three sub-phases that always run in the same order: G1, then S, then G2.

G1 phase, or Gap 1, is the interval between the end of the previous M phase and the start of DNA replication. The cell is metabolically active throughout. It grows in size, makes RNA and proteins, and builds up its organelles. What it does not do is copy its DNA. G1 is usually the most variable sub-phase in length, and it is the point at which a cell effectively commits itself to another round of division or steps away from one.

S phase, the synthesis phase, is the phase of DNA replication. The amount of DNA per cell doubles here, so a cell that had 2C DNA when S began has 4C when S ends. The next sentence is the one to fix in memory. The chromosome number does not change during S phase. A diploid cell that was 2n before S is still 2n after S. What changed is that each chromosome, which was a single thread, now consists of two identical sister chromatids joined at a common centromere. Doubling the DNA is not the same as doubling the chromosome count, because a chromosome is counted by its centromere and not by the number of chromatids attached to it. In animal cells a second duplication happens at the same time but out in the cytoplasm: the centriole duplicates during S phase.

G2 phase, or Gap 2, comes after replication is complete. Cell growth continues, and the proteins needed for the coming division are synthesised, including the tubulin from which the spindle will be built. Once the cell has its full complement of duplicated DNA and division proteins, it enters M phase.

G0, the quiescent stage, is not part of the main loop at all. Cells that will not divide again, or will not divide for a long time, leave the cycle from G1 and enter G0. A cell in G0 is fully alive and metabolically active. It carries on with its normal job, makes proteins, respires and responds to signals; it simply does not proliferate unless the body calls on it to do so. Heart muscle cells and mature nerve cells in adult animals are the standard examples of cells that essentially stay in this stage. Many other cells, such as liver cells, sit in G0 and re-enter the cycle only when tissue has to be replaced after injury or ordinary wear. Never describe a G0 cell as dead or dying; describe it as active but non-dividing.

It is worth noticing that the whole of interphase is really about making one cell fit to become two. Growth in G1 supplies the raw material, replication in S supplies the second copy of the instructions, and G2 supplies the machinery. Skip any one of them and the division that follows would be defective.

Mitosis is called the equational division because each of the two nuclei it produces carries exactly the number of chromosomes the parent nucleus had. It is divided into four stages, and each is best remembered by the single event that marks it.

Prophase. Prophase follows S and G2, so a cell entering prophase has already replicated its DNA. Chromatin, which was a long tangled thread, condenses and coils until each chromosome becomes a compact, visible body. Each of these chromosomes already carries two sister chromatids joined at the centromere, which is why chromosomes look double from the very beginning of mitosis. Meanwhile the centrosome, which duplicated during interphase, separates into two, and the two centrosomes move towards opposite poles of the cell, radiating microtubules as they go. These microtubules and their associated proteins form the mitotic spindle. By the end of prophase the cell has lost several familiar structures: the Golgi complexes, the endoplasmic reticulum, the nucleolus and the nuclear envelope are no longer seen. If a description tells you that chromosomes are clearly visible but the nuclear envelope has not yet broken down completely, that cell is in prophase.

Metaphase. The complete disintegration of the nuclear envelope marks the start of metaphase. The chromosomes, now lying free in the cytoplasm, reach their maximum condensation, which is why metaphase is the best stage for studying the shape and size of chromosomes. Each chromosome carries small disc-shaped structures on the surface of its centromere, called kinetochores, and spindle fibres from the two poles attach to the two kinetochores of a chromosome. Pulled from both sides at once, the chromosomes come to lie in a single plane at the equator of the cell. That plane of alignment is called the metaphase plate. Note carefully that the metaphase plate is a plane and not a structure you could isolate or stain.

Anaphase. One event opens anaphase: the centromere of every chromosome splits, and all of them split at the same moment. The two sister chromatids of a chromosome are no longer held together, and each of them is now a complete chromosome in its own right, called a daughter chromosome. The spindle fibres shorten and draw them towards opposite poles. Because the fibre pulls at the centromere, the centromere leads the way and the arms trail behind it, which is why the shape a chromosome takes at anaphase depends on where along its length the centromere sits. A centromere in the middle leaves two arms of equal length trailing behind it, giving a V. A centromere a little off centre leaves one arm longer than the other, giving an L. A centromere close to one end leaves a very short arm and a very long one, giving a J. A centromere right at the end leaves a single trailing arm, so the chromosome moves as a straight rod. Anaphase is also the moment when the chromosome count inside the cell temporarily doubles, a point worked out in full later on this page.

Telophase. The chromosomes have arrived at the two poles. They now decondense and lose their individuality, going back to being a diffuse mass of chromatin, so that individual chromosomes can no longer be made out. A nuclear envelope assembles around each of the two clusters, and the structures that vanished in prophase come back: the nucleolus, the Golgi complex and the endoplasmic reticulum all reform. At the end of telophase there are two complete nuclei inside one cell. Until cytokinesis finishes the job, it is still a single cell.

Karyokinesis leaves two nuclei inside one cell. Cytokinesis divides the cytoplasm so that those two nuclei end up in two separate cells. How it is done depends on one thing: whether there is a cell wall.

In an animal cell there is no wall, so the plasma membrane itself can be pinched. A furrow appears in the plasma membrane at the equator, deepens gradually and finally meets in the centre, cutting the cytoplasm into two. Because the process works from the outside inwards, it is described as centripetal.

A plant cell cannot do this, because a rigid cell wall cannot be squeezed inwards. Instead, wall material is carried in vesicles to the middle of the cell, and these vesicles fuse to make a cell-plate at the centre. The cell-plate then grows outwards until it reaches and joins the existing lateral walls of the parent cell, so plant cytokinesis is centrifugal, from the inside outwards. The cell-plate represents the middle lamella, the layer that will lie between the walls of the two adjacent daughter cells; each daughter later deposits its own wall material on its side of it. Organelles such as mitochondria and plastids are distributed between the two daughter cells as the cytoplasm is divided.

Now the significance of the whole process. Mitosis usually produces two diploid daughter cells whose genetic content is identical to that of the parent cell, so its value lies in making more cells without changing what those cells are.

Growth. A multicellular organism grows mainly by adding cells, not by making a fixed number of cells larger and larger. In plants, mitotic divisions in the meristematic tissues, that is the apical meristems and the lateral cambium, allow growth to continue throughout the life of the plant.

Restoring the nucleo-cytoplasmic ratio. As a cell grows, the volume of cytoplasm increases while the nucleus does not keep pace with it. One nucleus can service only so much cytoplasm. Dividing brings the ratio between nuclear and cytoplasmic material back to a workable value, and this is one of the standard reasons given for why cells divide instead of simply growing without limit.

Repair and replacement. Cells that wear out are constantly replaced by mitosis. The cells of the upper layer of the epidermis, the cells lining the gut and the blood cells are all replenished this way, and the healing of a cut is the same process working locally.

Finally, hold on to a precise version of what mitosis conserves. It conserves the chromosome number, not a label. A haploid cell dividing mitotically, as happens in some lower plants and in some social insects, gives two haploid cells; the number is still faithfully conserved, and the daughters are still genetically identical to the parent.

Meiosis takes one diploid cell and makes four haploid cells. It occurs in specialised diploid cells called meiocytes, the gamete mother cells, during gamete formation in animals and spore formation in plants. Two features define it. First, the DNA replicates only once but the cell divides twice, which is precisely how the chromosome number gets halved. Second, homologous chromosomes pair up and exchange parts, something mitosis never does. Meiosis I is the reductional division, in which the chromosome number is halved. Meiosis II is equational and closely resembles mitosis.

Prophase I is far longer and more complicated than mitotic prophase, and it is divided into five substages that always follow the same order.

Leptotene. The chromosomes gradually become visible as thin threads under the light microscope, and compaction continues through this substage. Nothing has paired yet.

Zygotene. The homologous chromosomes now begin to pair with each other. This pairing is called synapsis, and it goes together with the formation of a protein framework between the paired chromosomes called the synaptonemal complex. The structure formed by a pair of synapsed homologous chromosomes is called a bivalent, also called a tetrad. Both words name the same object but count different things: bivalent counts the two chromosomes present, tetrad counts the four chromatids present. The sex chromosomes also pair, although only along part of their length.

Pachytene. The bivalents are now clearly seen as tetrads, and this is the substage of crossing over. Structures called recombination nodules appear along the bivalent, and at these sites segments are exchanged between the non-sister chromatids of the two homologous chromosomes. Get that phrase exactly right. The exchange takes place between chromatids belonging to different homologues, not between the two sister chromatids of the same chromosome, because sister chromatids are identical copies and swapping material between them would produce nothing new. Crossing over is an enzyme-mediated process, and the enzyme involved is recombinase. By the end of pachytene the exchange itself is complete.

Diplotene. The synaptonemal complex dissolves, and the two recombined homologous chromosomes begin to move apart from each other. They do not separate completely, because they stay attached at the points where crossing over took place. Each such point of attachment looks like the letter X and is called a chiasma, the plural being chiasmata. Chiasmata are the visible evidence that crossing over has occurred. In the oocytes of some vertebrates diplotene can be extraordinarily long, lasting months or even years.

Diakinesis. The chiasmata now slide towards the ends of the chromosomes, a process called terminalisation. The bivalents are fully condensed, the nucleolus disappears, the nuclear envelope breaks down and the meiotic spindle assembles. Diakinesis is the transition into metaphase I.

Metaphase I. The bivalents line up on the equatorial plate. Here is the crucial difference from mitosis. Spindle fibres from one pole attach to the kinetochore of one homologue of a pair, and fibres from the opposite pole attach to the kinetochore of the other homologue. Each chromosome is therefore pulled from one side only, whereas in mitotic metaphase a single chromosome is pulled from both sides at once.

Anaphase I. The two homologous chromosomes of each pair are drawn apart to opposite poles. Their centromeres do not split, so every chromosome that travels to a pole still carries both of its sister chromatids. Which homologue of a given pair goes to which pole is decided independently for every pair, and that independent assortment is a second source of variation working alongside crossing over.

Telophase I. The nuclear membrane and the nucleolus reappear and cytokinesis follows, giving two cells known as a dyad. The chromosomes loosen somewhat but never return to the fully extended state seen in an interphase nucleus. The stage that follows is called interkinesis, and it is generally short. The most important thing to remember about interkinesis is a negative one: there is no DNA replication during it.

Meiosis II begins immediately after the cytokinesis of the first division, often before the chromosomes have fully elongated. There is no S phase in between, so a cell entering meiosis II has half the chromosome number of the original meiocyte, yet every one of those chromosomes still carries two chromatids. That single sentence explains everything meiosis II has to do.

Prophase II is short and simple. The chromosomes compact once again, and the nuclear envelope, which had reformed during telophase I, disappears a second time.

Metaphase II. The chromosomes line up at the equator of each of the two cells. Spindle fibres from opposite poles attach to the kinetochores of the two sister chromatids of every chromosome, exactly as they do in mitotic metaphase.

Anaphase II. The centromeres split at last. The sister chromatids separate from each other and move to opposite poles as independent chromosomes.

Telophase II. Nuclear envelopes form around the four groups of chromosomes, and cytokinesis gives the final product: four haploid cells, referred to as a tetrad of cells. Take care with that word, because it is used in two different senses in this topic. A tetrad in prophase I is a single bivalent with its four chromatids, while a tetrad at the end of meiosis is a group of four cells.

Why meiosis matters. The first reason is arithmetic. In sexual reproduction two gametes fuse, and if gametes carried the full diploid number, the chromosome number would double in every generation. By halving the number during gamete formation, meiosis makes sure that fertilisation restores exactly the diploid number characteristic of that species. So the process that reduces the chromosome number is the very process that conserves it across generations, which sounds contradictory until you put fertilisation next to it.

The second reason is variation. Two independent mechanisms inside meiosis shuffle the parental genetic material. Crossing over at pachytene produces chromosomes carrying a mixture of maternal and paternal segments, so no chromatid leaving meiosis need be identical to the one that entered. Independent assortment at anaphase I means every homologous pair decides separately which pole its two members travel to, so the combinations of whole chromosomes in the gametes differ as well. Between them, these two mechanisms let one individual produce an enormous variety of genetically different gametes. That variation is the raw material on which natural selection works, which is why meiosis is tied so closely to evolution.

One practical note to close with. In animals, meiosis produces gametes directly. In flowering plants, meiosis produces spores, and those spores then divide mitotically to build the haploid gametophyte, which is what finally produces the gametes. The reduction in chromosome number happens at meiosis in both cases; only the step at which recognisable gametes appear is different.

Most mistakes in this topic are counting mistakes, and nearly all of them come from mixing up three different quantities: the number of chromosomes, the number of chromatids, and the amount of DNA. Fix one rule in your mind and the rest follows on its own.

A chromosome is counted by its centromere. One centromere means one chromosome, whether it carries one chromatid or two. So when a centromere splits at anaphase, one chromosome instantly becomes two, and the chromosome count inside the cell rises even though not a single new molecule of DNA has been made.

Work through mitosis in a human cell, where the diploid number is 46.

In G1 there are 46 chromosomes and 46 chromatids, one chromatid per chromosome, and the DNA content is 2C. After S phase, and so all through G2, there are still 46 chromosomes but now 92 chromatids, and the DNA content is 4C. Prophase and metaphase change none of these figures: 46 chromosomes and 92 chromatids at both stages. At anaphase every centromere splits, so the cell contains 92 chromosomes and 92 chromatids, with 46 chromosomes travelling to each pole. After telophase and cytokinesis, each daughter cell has 46 chromosomes, 46 chromatids and 2C DNA, exactly where we started.

Now the same cell going through meiosis. The meiocyte replicates its DNA first, so it enters prophase I with 46 chromosomes, 92 chromatids and 4C DNA. Those 46 chromosomes pair up into 23 bivalents, and each bivalent is a tetrad of four chromatids. Metaphase I still shows 46 chromosomes and 92 chromatids, arranged as 23 bivalents on the plate. At anaphase I the homologues separate without their centromeres splitting, so 23 chromosomes move to each pole and every one of them is still double.

After telophase I and cytokinesis, each of the two cells has 23 chromosomes, 46 chromatids and 2C DNA. That combination looks self-contradictory at first sight, so take it slowly. The cell is already haploid, because haploid refers to the number of chromosome sets and only one member of each pair is now present, and yet it holds the same amount of DNA as an ordinary body cell sitting in G1. Haploid does not mean half the DNA of a G1 cell at this point; it means one set of chromosomes.

Prophase II and metaphase II keep those same figures: 23 chromosomes and 46 chromatids. At anaphase II the centromeres split, so that cell momentarily contains 46 chromosomes and 46 chromatids, with 23 heading to each pole. Each of the four final cells ends with 23 chromosomes, 23 chromatids and C amount of DNA.

Two generalisations let you apply all of this to any number you are handed. First, a cell with diploid number 2n forms n bivalents in prophase I. Second, at the end of meiosis I each cell has n chromosomes but 2n chromatids, while at the end of meiosis II each cell has n chromosomes and n chromatids. Substituting a diploid number of 24 gives 12 bivalents in prophase I, then 12 chromosomes with 24 chromatids in each cell after meiosis I, then 12 chromosomes with 12 chromatids in each of the four final cells. The arithmetic never changes; only the number you start with does.