Steve Jobs once said “death is very likely the single best invention of life.” Whilst the Apple mogul may have been contemplating life after his own death, it is also worth considering his words in the context of biological life. Apoptosis, the organised process by which cells kills themselves, is a fundamental part of life. It is required to build a human baby from a fertilised egg, to remove diseased tissue and to regulate organ function. These life-bearing consequences of a death process present a dramatic irony to apoptosis.
The importance of apoptosis in promoting life are emphasised by its dysregulation in cancer. Genes which function to inhibit the formation of cancer cells (tumour suppressors), such as TP53, are key to regulating proteins which control apoptosis. This gene and many like it are often mutated in cancer cells resulting in an inhibition to control apoptosis. Without the ability to die, these cells persist, multiply and form tumours. Apoptosis becomes entangled in life’s struggle for survival; your cells die so that you live on in the absence of disease.
When I first encountered the cell biology controlling apoptosis as an undergraduate I was fascinated by its complexity. Even now there are too many proteins involved to remember with more always being discovered. I find a good way to understand apoptosis is to think of it as a great film. This film is a cops and robbers action thriller. In fact, Martin Scorsese’s The Departed, may serve as a good example. In The Departed you have a mob boss (Costello, played by Jack Nicholson) and his criminal gang including Sullivan (Matt Damon). Trying to catch Costello in the act and put an end to organised crime is Queenan (Martin Sheen) and his Special Investigations Unit including Costigan (Leonardo DiCaprio).
Costello represents a group of proteins which activate anti-apoptotic proteins and inhibit apoptosis. These anti-apoptotic proteins are represented by his gang. He receives information which tells him that his gang must pull off a large money drug deal to ensure the survival of the gang. However, Queenan (representing an activator of pro-apoptotic proteins) catches wind of Costello’s intent and instructs his unit (pro-apoptotic proteins) to catch Costello’s gang in the act. This balance between the two sides is vital to determining the outcome. Complexity arises when Costigan and Sullivan go undercover for the opposite side in order to sabotage the others chances. If Sullivan wins then the gangs survival is ensured. But if Costigan triumphs than the gang is caught.
In other words, the balance of anti-apoptotic and pro-apoptotic proteins plays a vital role in determining cell fate. A tip in favour of pro-apoptotic proteins will activate apoptosis and induce cell death. The levels of these proteins are controlled by upstream transcription factors which receive survival/death signals and translate them into an acton. The point made by Costigan and Sullivan is that proteins from both sides interact with each other to inhibit or promote apoptosis. For example. the anti-apoptotic protein, Bcl-2, will inhibit the pro-apoptotic protein, Bax.
This perpetual interaction of proteins controlling apoptosis is tightly regulated in order to maintain cellular homeostasis. Loss of apoptosis regulation is a common theme across all cancers and highlights its importance in maintaining life. Our understanding of the biological processes controlling apoptosis has increased dramatically in the past two decades. By funding basic science research into apoptosis we can continue to find ways to fix apoptosis in cancer cells and develop new anti-cancer therapies.
Visualising apoptosis like a popular crime thriller may only work for some but hopefully it has emphasized the importance of the life/death balance with which apoptosis is forever entwined. By the way, they all die in the end.