Death. Morbid and depressing to most but a topic that fascinated me in college. A natural part of my everyday life. Before you report me to the Gardaí as a serial killer, zoom down to the microscopic level. Billions of our cells die everyday and many have been programmed to do so. A fine equilibrium is kept with new cells moving in to the vacant spaces. To find out what exciting developments are happening in this field of research, I caught up one of the most highly cited scientists in the world on programmed cell death, Prof. Seamus Martin of Trinity College Dublin.
It’s been 25 years since Martin began researching apoptosis after seeing an unusual morphology in the nucleus of Leukemic cells. After his PhD he made a deliberate switch to immunology and worked with the then emerging epidemic, HIV. He saw similar signs in HIV infected cells and was “dragged back into” apoptosis research. Martin explained that it is now known that “understanding cell death is fundamental to understanding diseases. In almost all major diseases you have a disturbance in cell death control. You either have too much cell death or too little cell death”.
Programmed cell death or apoptosis is effectively cellular suicide. Because of damage, old age or other circumstances, the cell initiates a set program that results in its death. Research in this area has been through its golden era of exploration. “It’s a good period in that we kind of understand the nuts and bolts of the process and that’s enabled to us to focus on what is really important”.
Developing Targeted Treatments
The central theme in apoptosis research is cancer as too little cell death results in a tumour. The mechanism of how this happens is now well understood so what is important to scientists at this stage is finding better targeted treatments. There are a number of key proteins involved in both initiating and preventing programmed cell death. Martin explains that “a lot of the focus right now is on trying to neutralise the pro-survivors of the BCL-2 family in cancer… because that effectively is what puts the brake on cell death”. These pro-survival proteins prevent the initiation of programmed cell death and tumours are often reliant in a mutation in one of these proteins for their continued survival. Neutralising these can tip the balance in favour of cell death.
One of the main challenges to cancer treatment is targeting the tumour and not promoting cell death in healthy cells in the body. Tumours are under intense pressure which is termed oncogenic stress. “It has evolved through this Darwinian process which means it has had to make a lot of compromises. This means it has a lot of addictions which it has traded in order to extend it’s survival”. These addictions are mutations in proteins such as members of the BCL-2 family. Targeting these altered molecules can enable tumours to more readily succumb to programmed cell death and will also have less impact on healthy cells.
Another class of compound, IAPs (inhibitor of apoptosis proteins), surprised many researching in this field. These proteins prevent some proteins, caspases, involved in apoptosis from working. It turns out that IAPs can be effective at promoting cell death in tumours. Why is this surprising? Scientists were puzzled as IAPs do not prevent apoptosis as they are part of a process downstream of the main suicide instructions. At that stage, cells are already doomed to die. After investigation “it turns out that with some tumour cells they are for some reason prone to killing themselves by upregulating TNF (Tumour necrosis factor)”. Their ability to increase the amount of this protein that promotes cellular suicide makes them perfect drug candidates and some are currently at the clinical trial stage.