A blog about microbes, diseases and biomedical research advances. Posts in English or German.
An adult’s body is made up of an estimated 37 trillion human cells, and billions of these cells die every single day. This is a natural process to keep our organs and bodies healthy and working. Interestingly, these cells commonly die in a very uniform and regulated way: a process that its discoverers termed apoptosis.
Our body has incredible mechanisms to handle the daily mass of dead cells. Apoptotic cells go through a process of ‘blebbing’ when they die – they fall apart and form small pieces which can be taken up by other cells. Specialised cells, so called Macrophages, ‘eat’ the tiny fragments of the dead cells and digest them. The material that is recycled in this process can be used to build new cells, starting the cycle over again.
This very elegant system helps our bodies to get rid of cells without harming the whole organism. But it is not the only way cells can die. Another long known death mode is not as gentle: Necrosis. Necrotic cell death is often caused by outside stimuli, like toxins or burns. And necrotic cells tend to go with a bang, in the form of massive inflammation. Have you ever seen pictures of brown recluse spider bites? If the answer is no, try to resist searching for images (unless you don’t mind nightmares and episodes of arachnophobia). Let me summarize it for you: Recluse spiders produce a venom that can cause black, necrotic skin lesions. A bite rarely becomes necrotic, but when it does, it is not pretty but rather painful and also slow to heal.
While apoptosis is often described as cellular suicide, necrosis was classically seen as a forced and unregulated mechanism. Together with a third form, autophagic cell death, the death triumvirate was complete. For a while, we thought we had discovered all cell deaths there were. But not for long: today, we know more than 10 distinct cell death modes (and this number is steadily growing), and we are starting to understand some of their molecular mechanisms.
Does it really matter if there are three or 20 different ways for a cell to die? Well, if you want to understand diseases and find new ways to treat them, it surely does. Cancer cells often prevent apoptosis in one way or the other in the process of becoming cancerous. Similar to a clockwork, one faulty part can block the whole system. One faulty component of the apoptosis pathway can enable the cells to escape the cellular suicide drive. If we want to get rid of these cells, we can either focus on repairing and stimulating their apoptosis mechanism or we try to kill them by other means. Necrosis is often not a favourable way to eliminate cancer cells because of its effect on the body: pain, swelling, inflammation. If we know enough about other cell death modes and their mechanisms, we can try to target them for therapy.
Sometimes, a disease might even be caused by a block one of these cell deaths. Changes in necroptosis, a regulated form of necrosis, may have a role in illnesses such as brain diseases and infections. Restoring necroptosis could be a good treatment option in these cases.
One of the newest additions to the cell death portfolio is ferroptosis; another necrotic process that depends on intracellular iron. The metal causes this mode of cell death by making reactive oxygen – a harmful form of the oxygen we breathe that can severely damage and kill cells. A recent report links ferroptosis to kidney injuries [study not openly accessible] caused by temporary problems of oxygen supply. The researchers from this study found that a chemical that blocks ferroptosis could prevent a great deal of the kidney damage in this setting.
The more we learn about all the different flavours of cell death, the more we begin to understand that they form a network with overlapping regulators. Take the protein p53 as an example: it is famous for its role as apoptosis regulator, and it is commonly mutated in cancer. 50% of human tumour cells either have no p53 or mutated p53 which is unable to induce apoptosis. Mutated p53 may, however, keep some of its other functions. One specific mutated p53 that is stripped of many of p53’s most well studied functions (stopping cells from growing and coordinating apoptosis) can still induce ferroptosis [study not openly accessible]. Maybe some p53 mutants that are commonly found in cancer can do too. And perhaps, someday, we will be able to use these and similar insights to develop new, targeted therapies for a variety of diseases.