Copy it all, then split it fairly.

From DNA to chromosome.

Step up through the four levels of packing in the 3D model: the bare double helix (2 nm), nucleosomes (11 nm), the coiled fibre (30 nm) and the condensed chromosome (about 1400 nm). Turn the labels on and read the width at each level.

• DNA: one chromosome contains one very long DNA molecule (before S phase). The genes are sections of it.
• Histone proteins: positively charged proteins that the negatively charged DNA winds round, making nucleosomes. They package the DNA so it fits in the nucleus and can be condensed without tangling.
• Sister chromatids: after replication in S phase a chromosome is two chromatids, each one DNA molecule, with identical base sequences.
• Centromere: the region where the two sister chromatids are held together; spindle fibres attach here (at the kinetochores) during mitosis.
• Telomeres: long runs of a repeated, non-coding base sequence at each end of the chromosome.

In interphase the chromatin stays loosely packed so genes can be transcribed, which is why separate chromosomes cannot be seen in a non-dividing nucleus.

The cell cycle.

Press Start and watch the pointer go round. Note the DNA per cell on the graph: it stays at 2 units through G₁, climbs to 4 units across S, and falls back to 2 when the cell divides. Try Damage the DNA and Leave for G₀.

Why mitosis matters: the two daughter cells are genetically identical to each other and to the parent cell, because each receives one copy of every chromatid. That is exactly what is needed for:

• Growth of a multicellular organism, from zygote to adult, by increasing the number of cells.
• Replacement of damaged or dead cells, such as red blood cells and skin cells, with identical cells.
• Repair of tissues, such as a healing cut or a broken bone, by cell replacement.
• Asexual reproduction, such as yeast budding or new potato plants from tubers, giving offspring that are clones of the parent.

Mitosis also makes clones of a selected lymphocyte during an immune response. Cells that specialise usually leave the cycle after G₁ and enter G₀.

Telomeres guard the ends.

Choose body cell and press Divide ×10 a few times, watching the telomere length (in kb per end) and the genes intact. Then repeat for the stem cell, the cancer cell and the imaginary chromosome with no telomeres.

• The end-replication problem: DNA polymerase cannot copy the very end of a linear DNA molecule, so each time the DNA is replicated a short length is lost from the ends.
• The role of telomeres: because the ends are non-coding repeats (TTAGGG in humans), the lost DNA comes from the telomere, not from genes. Telomeres prevent the loss of genes during replication.
• The limit: in the lab a body cell loses about 0.1 kb per end per division; after about 50 divisions the telomeres are critically short and the cell stops dividing, before any gene is lost.
• Telomerase: stem cells, and most cancer cells, keep the enzyme telomerase active, which adds repeats back on to the ends.

Stem cells replace and repair.

Let the epidermis run, then press Graze the skin and watch the stem cells in the bottom layer speed up. Reset and try Deep burn, which destroys the stem cells in the wound.

• Stem cell: an unspecialised cell that can divide by mitosis again and again, and whose daughter cells can differentiate into specialised cells.
• Replacement: in the skin each stem cell division gives one new stem cell and one cell that moves up, differentiates and is eventually shed, so loss is balanced.
• Repair: after a graze the stem cells divide faster. Every new cell is made by mitosis, so it is genetically identical and the tissue is rebuilt correctly.
• Other examples: stem cells in the bone marrow replace red and white blood cells; stem cells in the gut lining replace cells worn away.

When division goes out of control.

Start the clock with low carcinogen exposure, then raise it, or press Mutate the centre cell twice. Watch the counters for cells with one mutation and for tumour cells, and the state of the tissue.

• Normal control: genes control the cycle. Proto-oncogenes stimulate division; tumour suppressor genes stop the cycle or trigger cell death (apoptosis) when the DNA is damaged.
• Mutation: carcinogens such as tar in tobacco smoke, UV light and ionising radiation increase the mutation rate. A mutated proto-oncogene (an oncogene) or an inactivated tumour suppressor gene removes a brake.
• Tumour: a cell with the right combination of mutations divides by mitosis repeatedly and without control. All its descendants carry the same mutations, so a mass of cells, a tumour, forms.
• Benign or malignant: a benign tumour stays in one place; a malignant tumour invades nearby tissue and cells can spread in the blood or lymph to form secondary tumours (metastasis). Cancer is a disease caused by malignant tumours.