A Cell’s Life: In the End
Source: flickr.com/photos/dhedwards/
The beginning of the end
Cells, like humans, go through a cycle of life – they are born, they reproduce and eventually they die. These life events are controlled by specific genes that are turned on and off during the course of a cell’s life. Events like cell birth and cell reproduction are easy to see as being active processes, but cell death was largely seen as a passive, inevitable event.
Over years of study and experimentation, what once was considered a passive event started to look more like active suicide. Researchers found that cell death could be delayed or blocked altogether by inhibiting certain genes and proteins. The study by Kerr, Wylie and Currie (1972) summarized and reported on the changes that occur to a dying cell using electron microscopes. They discovered that there are two distinct steps or stages in cell death: the death itself (suicide) and clean-up of dead cells by neighboring, healthy cells. Another major step forward for the field was the discovery of the exact order of genes that are required for cell death in microscopic worms, which was eventually found to be universally true for all animals (with some differences between species).
Making the decision to die is not to be taken lightly – after all, whatever function that cell had will no longer be available once dead. There are two environmental conditions that can lead to cell death. The first is during the normal development of an organism. Take your hands for example. The spaces between your fingers were once filled with cells that were eliminated through controlled, programmed cell death. This is why your fingers do not look like the webbed feet of ducks (for ducks, the cell death does not happen, hence the webbed feet). Your nervous system (and that of other vertebrates) produces many more neurons than it initially needs and over time, the ones that fail to make a connection and find a partner die off. Even non-mammalian animals need cells to die for proper development: tadpole tails are removed by cell death during their metamorphosis to adult frogs.
A second condition for cell death to occur is in response to environmental stress. Cells do not live in isolation from the environment and must deal with its conditions every day. Sometimes, these conditions prove too difficult for the cell to continue living: too little food, too much radiation, too dangerous for surrounding healthy cells. Damaged or otherwise unhealthy cells are a threat to their neighbors as they can leak out toxic products, affecting its neighbors. If this is the case, a cell can press its auto self-destruct button and commit suicide, sacrificing itself for the greater good of the world that it lives in.
How cells commit suicide
I referred to cell death as suicide above because research has shown that although the process of dying is started by external influences, it is continued and executed all internally – that is, inside the dying cell. An environmental trigger – like radiation, starvation or hormones – switches on the self-destruct sequence of a cell. In the regular version of cell death (commonly called apoptosis), DNA inside the cell is chopped up, followed by dismantling of the cell’s proteins before ultimately being swallowed by neighboring cells. But there is an alternate form of cell death (called autophagy), which involves cells digesting parts of themselves. Eating the less vital parts of one’s own body (or cell parts in the case of a cell) has the benefit of prolonging its life in case conditions improve, giving the cell a chance to reverse the process and resume its normal life. Because the process of suicide is irreversible, the decision to start down the path of suicide must be made with the utmost care.
Why do cells commit suicide?
A cell might die for a variety of reasons. Like all life on earth, cells have a finite time in existence. They are born, can grow old (a process called senescence) and eventually give way to the next generation of cells. In the case of cells, this final stage happens to be more active and immoral from a human-centric point of view: in essence, the cells die because all the other cells around it are telling it to die. The old cell gives into social pressures and decides to ease the pain. However grim this might sound, there are actually some benefits for a cell to die this way. The first is that it prevents any leakage of potentially harmful substances (for example, the power plant of the cell, the mitochondria, is filled with death-inducing proteins). It is like pre-emptively replacing an aging car before it breaks down and leaves you stranded in the middle of nowhere. A second reason for dying this way is that any usable material in the cell can be recycled or reused. If we extend the car example, it is akin to taking parts of the old car to build or add to an existing car. The death of a cell can serve to nurture and strengthen the remaining cells. This appears to be the case for developing eggs in the microscopic worm Caenorhabditis elegans.
A more sinister form of death: murder in cells
Up until recently, research has focused on how cells commit suicide. But more recent experiments are beginning to uncover a darker side of cell death: cell murder. Earlier, we defined cell death as a suicide because the process of dying is all internally controlled. But in cell murder, cell deaths are unable to continue unless some external signal allows them to do so. At least this is what I found in my research on cell death in microscopic worms. There is a gene which is required for cells to die in response to radiation stress – and this gene is required after the cell death process is started in these cells. Because cell suicide occurs internally, any genes and proteins required for the process would be functioning inside the cell. But the gene that I was working with worked from healthy cells surrounding the dying cell – more convincing evidence that cell death is not always suicidal and that murdering of cells can take place. To my relief a similar phenomenon was observed by a different research group in a different cell type (but the same microscopic worm), which I take as a good sign that what I found is not an isolated artifact.
Source: flickr.com/photos/pulmonary_pathology/
So why does it matter?
So far we have discussed cell death as a process that occurs naturally during development and as a consequence of external, environmental stresses. But what consequence does this process have on humans? Or, why does it matter?
A major consequence of abnormal cell death is cancer. If cells that are supposed to die fail to die, we are one step closer to creating cancerous cells. On the other hand, if healthy cells start dying randomly – as in the case during degenerative diseases – we can end up with diseases such as Alzheimer’s disease. This is why research on what makes cells die is so important. And the insight that cell death can be caused from surrounding cells is a major conceptual step forward in thinking about how to treat these conditions.
If we consider that traditional cancer drugs target the cancerous cell for death, we have the challenge of finding and targeting that exact cell. However, scientists are beginning to realize that it is not a simple matter of one cell or type of cell that can be targeted for cancer treatment. Instead, they are talking about a tumour microenvironment – essentially a collection of different types and kinds of cells all working together to create cancer. It is possible that targeting just one type of cancerous cell with a drug would not have any effect on eliminating the cancer. But what if we could tell healthier cells surrounding the cancerous cells to kill – murder – their cancerous neighbors? We know that some cell types respond to such a command in microscopic worms. Perhaps cells in humans do as well and if that is the case, it could open up new avenues of research for both academics and pharmaceutical companies alike.
The future of murderous cells
The first step would be to figure out what kinds of proteins and genes are involved in this murderous process. Because the main genes and proteins that control cell death are similar between many organisms, what we find to be true in one organism may not be too far from the truth in another. If we know what these murderous proteins look like, we can produce synthetic mimics that would have the same killing effect. Combining this with what we know about targeting cancerous cells, one possible application of such knowledge could be used to target these murder proteins (or mimics) to cancerous cells so that they essentially kill each other – leaving the unaffected cells intact. Or these murderous proteins can be targeted to healthy cells, which would then deliver it to neighboring cancerous cells. More research is needed to determine whether such an application is possible, but it does open up new ways of thinking about the mysteries of cell death.
excellent article. and the 'layman' understands something so complex!
Thank you very much! I am happy to hear those words from you - hopefully the next pieces will be the same!
truly amazing, you have opened parameters that are paradigm-changing. visionary science at its best, thank you.
Thank you. I hope that there will be a move towards exploring other mechanisms of cell death in the future.
[...] on from his last article, “A Cell’s Life: In the End“, where Shu described the life cycle of cells, here he delves into the process in more [...]
[...] certain companies and interests, via financial market mechanisms looking to satisfy the economic organism, and it was done in the name of market health. In the name of the economy’s well being. [...]
[...] The series provides incredible and revealing closeups of human and non-human life, from cells to organs to obscure body [...]