1 Radiobiology basics

1.1 Introduction

The aim of this chapter is to provide a basic understanding of the cell’s life cycle and the difference between normal and cancerous cells. This information is instrumental for preparing a radiation treatment plan to fight the proliferation of cancer cells with photons, charged particles, or neutrons, as discussed in Chapters 2–5. In addition, we discuss here the relationship between radiation dose and cell survival rate, which is pivotal for the following chapters on radiation therapy. More details on the cell cycle can be found in standard biology [1] or physiology textbooks listed under “Further reading.”

Genes and a number of messenger proteins determine when and how quickly cells grow, when they divide (mitosis) and when they die (apoptosis). Some cells only live very briefly, such as the cells in the epithelial layer of the intestine (1.5 days). Other cells have a fairly long life span, such as the skin epidermis cells (20 days) or the red blood cells (up to 60 days). Some cells live long like osteocytes (25–30 years), and some cells never die like nerve cells. The cells that die over time need to be replaced. Those who never die cannot be recovered even if injured, which is the problem with spinal cord injuries. For unknown and uncontrolled reasons, a normal cell can suddenly turn into a dysfunctional cell that overrides all life cycle rules and death of a “normal” cell. Then the cell becomes cancerous. Radiation therapy is currently one of three methods of fighting cancer cells; the other two methods are chemotherapy and surgery. These procedures can also be referred to as “burning,” “poisoning,” and “cutting.” Although radiation treatment of tumor cells has seen tremendous development and refinement in recent years, it may not be the ultimate solution to fighting this disease. At the same time, enormous progress has been made in understanding the cell “machinery” so that biochemical cancer therapy through targeted drugs or immunizations is foreseeable in the near future. The Nobel Prize in Medicine 2018 was awarded to James P. Allison and Tasuku Honjo “for their discovery of cancer therapy by inhibiting negative immune regulation” [2]. Immune therapy of cancer is a novel and promising direction. But for the meantime, radiation treatment of cancer remains the second-best solution.

1.2 Life cycle of cells

The normal life cycle of cells can be subdivided into two main phases: interphase and mitotic phase (M); see Fig. 1.1.1 The interphase and mitotic phase constitute one cell cycle. During the interphase, normal cell activity occurs, including growth and DNA replication. The interphase occupies 90% of a cell cycle. The remaining 10% go to the mitotic phase, where the cell divides itself into two identical copies. After cell division is completed, both cells have the exact same genetic information, and the interphase starts over again, simultaneously in both new cells.

Fig. 1.1: Life cycle of a cell. G1, growth phase; G0,  rest phase; CP1, first check point in G1 phase; S, replication phase; G2, second growth phase; CP2, second check point in G2 phase; M, mitosis. The mitosis or cell division phase is subdivided into four subphases: prophase, metaphase, anaphase, and telophase. Red flags indicate checkpoints. At the end of the telophase, two identical new daughter cells are formed.

The life cycle of cells begins with the growth phase G1, in which the cell enlarges and synthesizes new proteins. Toward the end of this phase, a checkpoint (CP1) controls stop or go to the next phase. In case of stop, the cell goes into a rest phase G0. It remains there until called upon, for instance, for repairing injuries. Most body cells are in the rest phase G0 and fulfill their specified duties. The cell will complete the cycle and divide if the checkpoint gives a green light. For cell regulation, the checkpoint is essential. If the stop signal is overwritten in any way, uncontrolled replication of the cell can result, as we will see later.

The total genetic information is contained in any cell and is encoded in double-stranded DNA molecules. The genetic information of humans, the genome, is written in 46 chromosomes, each one containing one long DNA molecule. These 46 chromosomes come in 23 homologous pairs; one of each pair is inherited from the mother and father. Both chromosomes in a pair contain essentially the same genetic information governing the basic function of organs. This is true for the first 22 chromosomes. However, the 23rd pair is different for female (XX) and male (XY), determining the sex. Three pairs of chromosomes in their G1-phase are sketched in Fig. 1.2(a), representative of all others.

During the S-phase, cells replicate their genetic material, ensuring that each daughter cell will receive an exact copy during the mitotic phase. The two strands are copied in opposite directions (leading and lagging strands) during DNA replication using different transcription methods (for more information see Infobox I). After replication is completed, the DNA condenses into chromosomes. The chromosomes are a heavily coiled and folded-up version of long DNA strands. Only in this condensed phase can chromosomes be recognized by an optical microscope. Otherwise, the thin DNA chains do not offer sufficient contrast to be recognized. Each duplicated chromosome has two sister chromatids (joined copies of the original chromosome), which separate during cell division. The sister chromatids are attached to each other by a centromere; see Fig. 1.2(b). The centromere is a narrow “waist” of the duplicated chromosome, where two chromatids are most closely attached. Centromeres are important for organizing the associated chromatids in the cell and for their mechanical separation in the mitotic phase. Once separated by cell division, the chromatids are called chromosomes.

Fig. 1.2: Cell division starting from the G1-phase to the end of the M-phase. (a) In the G1-phase, all 46 chromosomes appear in homologous pairs; only three representative ones are sketched. (b) In the S-phase DNA replication and synthesis takes place, which condenses to sister chromatids in the prophase at the beginning of the M-phase. (c) In the anaphase, the sister chromatids are pulled apart to opposite halves of the cell. (d) In the final telophase, complete separation and generation of two new identical cells occur.