Getting a bird’s eye view of cell death
Cells die in your body every day. It’s a natural process by which damaged or old cells are taken away, allowing tissues to renew. But if the balance between cell growth and death becomes disturbed, that can cause problems. In cancer, a tumour can form if cells don’t die when they are damaged, and in degenerative conditions like Alzheimer’s disease cells die before their time and tissues can lose function. Meanwhile an acute event like a heart attack or stroke can trigger the death of cardiac or brain cells en masse.
A type of cell death called apoptosis is the focus of Prof Jochen Prehn’s lab at the Royal College of Surgeons in Ireland, where they are getting a bird’s eye view of the molecular pathways that initiate various cell death programmes in the body.
There are many questions to be asked: How are the pathways triggered? Can the trigger be stopped? Or can the trigger be enhanced so it works even better?
By building up a better knowledge of what kick-starts apoptosis, it will help us understand the impact of cell death in disease and injury, and it could ultimately allow scientists to ‘tell’ cancer cells in the body to die, or to protect vulnerable cells in degenerative disease by increasing their resistance to apoptosis.
Tackling such fundamental questions about how cells live and die needs a rounded view of what is going on, and the RCSI team can examine single cells in detail using high-powered and high-throughput microscopes. By tracking the cells over time, researchers can watch how they behave and build up a mathematical model of the ongoing pathways.
An industry supplement from SFI has enabled this ‘systems’ approach of analysis, particularly by bringing software engineer Heinrich Huber on board, where he has applied maths to the biological questions being asked.
This approach looks at organs and cells as systems - much as an engineer would view a manufacturing plant as a system - so each functioning part is analysed in detail to figure out its role in the overall cell or tissue.
In apoptosis that means looking in quantitative detail at each component of the pathway that triggers cell death and increases cell survival. One way is to measure the levels of specific proteins in the cells, which tells scientists about which genes are being switched on or off. Then the information gets fed into a collaborative model to give a more ‘systems’ view and the researchers can figure out the roles of particular genes and proteins in triggering cell death.
It’s a complex task, but getting to that level of understanding means you can better predict if a cell is going to go into apoptosis and die, which has important applications for clinical treatments.
In the pharmaceutical industry, understanding the predicted cellular response to a candidate drug could streamline the process of drug discovery and perhaps bring more effective drugs to market more rapidly.
In cancer if it could be predicted whether a particular tumour cell type would die when subjected to a given treatment, it could help to tailor more effective treatment regimes for the individual patient.
And ultimately an ‘apoptosis inhibitor’ might be developed to help protect cells from becoming collatoral damage in a stroke or heart attack.
But to get there needs a co-ordinated approach from many different mindsets, according to Prof Prehn, who is professor of physiology at RSCI.
“The work in this area has underlined the benefit of engineers and mathematicians working with biologists to understand biological questions,” he says.
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