Why do we need ‘programmed cell death’ (apoptosis)?

This essay was written by Muhammad Ashraf and was first published in the 2009 Mill Hill Essays.

Apoptosis, a form of programmed cell death, is a genetically regulated cell-suicide mechanism that is essential for our well-being. In this process, cells acquire the means of their own destruction in the form of an arsenal of deadly proteins, which they turn upon themselves. Usually apoptosis is for the good of the organism. It is required in biological processes such as embryogenesis and homeostasis (maintenance of a stable body). It also destroys cells, which may present a risk to our health, such as cells, which have undergone DNA damage. Its importance is shown by considering the serious consequences of reduced apoptosis. Tumours often form because of cancer cells developing the ability to suppress apoptosis, making them immortal and very dangerous. The other extreme, when too much apoptosis occurs, is thought to play a role in the development of diseases such as Alzheimer’s and in the massive destruction of lymphocytes in AIDS and in the adverse consequences of heart attacks.

As humans, we rely on apoptosis taking place properly throughout our lifetime. It first occurs in foetal development. The growth of an organ at this stage is often preceded by the extensive division and differentiation of a particular cell; apoptosis of excess cells can then ‘sculpt’ the resultant mass into the desired shape of organs. It also helps carve out the interdigital space between the fingers and toes, at about sixteen weeks into pregnancy. In rare occasions this process remains incomplete, causing a condition called syndactyly, where webbing remains between digits which are consequently fused together. Apoptosis also plays an important role in the development of the nervous and immune systems. Following the overproduction of many kinds of cells, nervous cells that fail to establish functional synaptic connections experience apoptotic death. Lymphocytes (white blood cells that are a major part of the immune system) that are potentially damaging to the body or ineffective due to a lack of productive antigen specificities also suffer the same fate. Apoptosis is vital for the removal of activated T lymphocytes following a cell-mediated immune response. If allowed to remain, these cells may attack an individual’s body constituents; this can result in autoimmune diseases where the immune system attacks the body’s own tissues. Evidently, the removal of certain cells from our body is crucial to our early development.

Maintaining an equilibrium between cell proliferation and cell death in our body is very important and apoptosis plays an integral role. In adulthood, an incredible ten billion cells die every day, roughly seven million cells a minute. This occurs simply to keep balance with the new cells being formed. This balance, or homeostasis, is a process that is not passive, but is regulated through apoptosis. Unlike necrosis (cell death through acute injury resulting in inflammation), apoptosis proceeds with cell shrinkage and fragmentation followed by phagocytosis (engulfment by a specialist scavenger cell). This allows cell contents to be reused and is also non-toxic, providing a very efficient method of removing considerable quantities of cells – essential for our daily needs.

Excessive or reduced apoptotic responses can have potentially fatal consequences. Cancer is a disease that is often characterized by a lack of apoptosis. Cancer cells are able to live on and continuously replicate themselves by evading the cell-suicide process, leading to the formation of tumours, typically because these cells possess a number of mutations. The mutations not only allow them to become more proliferative than normal (by ignoring cellular signals regulating their growth), but also prevent them from undergoing apoptosis, the normal response to DNA mutations. Research suggests that mutations in certain genes, such as the p53 gene, are pivotal to the development of tumours. Interest in the p53 gene in particular has grown recently as it has been found to be an especially important tumour suppressor gene. It is often damaged in cancer cells, preventing apoptosis from occurring and causing the development of potentially deadly tumours. This underlines the significance of apoptosistriggering genes: a greater knowledge of how apoptosis is regulated in tumour development would undoubtedly help in the development of treatments for cancer.

Apoptosis can also become less tightly regulated, often with ageing, leading to exaggerated responses to DNA damage. In neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, apoptosis is thought to account for much of the cell death and progressive loss of neurones. A further example of the detrimental consequences of unregulated apoptosis is seen in heart attacks following ischaemia, the reduction of blood flow to body tissues generally caused by blood clots. The heart attack induces apoptosis of cardiac muscle cells and can result in heart failure. Apoptosis also plays an important role in the depletion of CD4+ T lymphocytes during the progression of HIV infection to AIDS. Although a mere one in 100,000 CD4+ T lymphocytes are infected with HIV in a patient’s blood, many more are dying through apoptosis. These diseases result from excessive apoptotic activity. Clearly, we require programmed cell death and depend upon it being properly regulated and controlled to prevent grave outcomes.

Interest in apoptosis has surged since its discovery in 1972, as a result of our increased recognition of its immense significance in our health. Without programmed cell death, we would be unable to survive; body parts like our organs and limbs would not form correctly and our immune and nervous systems would not develop properly. Its implications in a range of diseases including AIDS, degenerative diseases, autoimmune diseases and particularly cancer, have led to its emergence as one of the foremost fields in biomedical research. An ability to manipulate this extraordinary process of apoptosis successfully could well become central to medical science, indicating its importance to our well-being.

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