Inducing Apoptosis- Countdown to Self-Destruction
By Susan Turrell, University of Leeds
From very early on in its life, a human cell is destined towards a particular fate. This job could be conducting electrical signals along a neural circuit, travelling through the body’s system of blood vessels on the lookout for harmful pathogens, or sensing light that has been focussed onto the retina of the eye, allowing us to visualise the world around us. But what happens if this pre-established plan goes wrong? What if this cell becomes infected with a malicious micro-organism, or if a vital signalling pathway becomes erratic and unstable?
Like an ageing car, if the cell is too damaged or dangerous to mend, it’s seen as a write-off and needs to be scrapped. Fortunately, every cell in our bodies has instructions for a self-destruct program maintained within its DNA. If it can’t be mended, events are set in motion that culminate in the termination of that cell. This process is called apoptosis.
Apoptosis is a neat and precise method of eradicating cells in a multicellular organism. It involves the systematic shutdown of the cell, and occurs in an ordered sequence. First, the material in the nucleus, called chromatin, condenses and the cell shrinks and contracts. Second, the nucleus disintegrates and the structures inside the cell fragment. Finally, small enveloped pieces of the cell break off in a process called blebbing. The cell has essentially been packaged up into parcels called ‘apoptotic bodies’ for immune cells to engulf and dispose of.
However, apoptosis is not just a method of ‘clearing up’ damaged cells. The cells in our bodies are multiplying and dividing all the time, and yet we don’t just keep on getting bigger and bigger. Programmed cell death balances out this growth so that the number of cells in our bodies stays relatively constant. Apoptosis is also a fundamental part of development in the foetus. It is essential for sculpting individual digits by removing the webbed tissue between our fingers and toes. It’s also important in the developing nervous system. When they’re growing, several nerve cells all strive to form a connection to a corresponding nerve or muscle cell. Those that make contact can transmit electrical impulses to stimulate movement or sensation, while those that fail to reach are eliminated.
So what’s the mechanism behind this process? This countdown to controlled self-destruction is triggered in two ways. The cell can receive an external signal from other cells, or the process can be kick-started from within. For example, receptors on the cell surface await a signal from immune cells which are like sentries, patrolling for potentially dangerous fugitives lurking inside cells. When they recognise that a cell is harbouring pathogens such as viruses or bacteria, the immune cells release factors which cause the infected cell to commence its ‘suicide program’. As well as this system, sensors inside the cell such as the protein p53 act as wardens for irreparable cell damage. p53 effectively performs an M.O.T on the cell by inspecting the DNA contained in nucleus. Depending on the level of any damage found, it either directs the repair of the affected DNA strand, or activates the self-destruct program. It does this so that any damaged DNA is not copied and passed on when the cell divides. Once these cell sensors are activated they start a cascade that amplifies the ‘death signal’ so that it cannot be switched off. The signal gets passed along to different proteins like a baton in a relay race, but each protein has several batons and so each handover involves more and more runners. In this way the cell becomes committed to the death program and can’t recover.
The final runners in this relay are a group of proteins called caspases. Caspases are expressed as inactive enzymes and have evolved to chop up other proteins when they get switched on. The termination signal is passed from ‘initiator’ caspases down to ‘executioner’ caspases, which are the bulldozers of apoptosis. These enzymes set about dismantling the structural components of the cell and this deconstruction leads to the breakdown of the cell contents.
When apoptosis stops working it can have disastrous results. One consequence is the uncontrolled growth of cells, leading to cancer. Cancer is caused by multiple mutations in different types of genes, and one of the most common proteins affected is the guardian of the genome, p53. If defective, this protein can’t activate apoptosis, and therefore cells that already have damaged and mutated DNA are allowed to multiply. Lots of cancer cells also have mutations in proteins involved in the apoptotic signalling cascade, so they can grow even when the cell is instructed to commit suicide.
I’m currently developing a gene therapy vector to treat cancer. This involves transporting a gene for a protein called TRAIL into cancer cells. TRAIL recognises cells that are carcinogenic and binds to cell surface death receptors. This activates the apoptotic signalling cascade from the outside. If successful, this therapy would be specific to cancer cells, so would have fewer side effects than conventional cancer therapies. However, as some cancers have damaged apoptotic pathways, this treatment won’t be useful for all cancer types. I like the idea behind this potential therapy because we are using the body’s own defence system to kill the cancerous cells, we just give it a little extra ammunition.
Apoptosis is one of the mechanisms that maintains the balance between growth and stasis, health and disease. This balancing act is vital, as a problem in a tiny element of this pathway can have a massive detrimental effect. The body has evolved a way to sacrifice defective parts for the benefit of the whole organism. For this reason, each individual cell holds the seed to its own destruction.
