The many faces of cell death: how death makes life possible

Only recently we are beginning to understand the many ways in which cell death operates and how they are intertwined. Two Belgian experts from the University of Ghent share their views on cell death and health: professor Peter Vandenabeele and PhD student Alex Vervaeke. What are their latest insights from fundamental research? And what exciting new applications do they offer for medicine? 

Kathelijne Bonne. English edition of an article first published in Dutch in the Belgian science magazine EOS Wetenschap (11/2025). 

Death terrifies. It scares to death. It is the dark opposite of life, which is the wonderful miracle studied by biologists. Therefore, one can understand that scientists have long ignored the phenomenon of cell death, even though it is an indispensable part of life. Without death, at all levels, there is no life, biology professor Peter Vandenabeele says.

Complex polyphony of life

Despite death's dreadful image, in nature, death is not an end point or a failure, but one of countless tiny steps in an endless cycle in which nothing is lost. At the cellular level, this cycle is not a simple linear path, but a complex polyphony through which waves of signals, molecules, triggers and cascades of reactions flow across a multidimensional network, with or without a noticeable effect on our well-being. 

However, there can be too much cell death, as in Alzheimer's disease or when we get infected by a toxin like anthrax, or not enough of it, as in cancer. New insights are opening doors to treatments that control cell death and, among other things, make tumours more visible to our immune system.

White blood cells are the first aid helpers

But before looking cell death in the face, we wondered what the immune system is, as it is crucially intertwined with cell death processes. Alex Vervaeke is doing his PhD under guidance of professor Mohamed Lamkanfi (Ghent University), a former student and colleague of Peter Vandenabeele. 

Alex investigates how spores of the Anthrax bacterium – the substance contained in a "powder letter" – cause cell death and how our immune system responds to it.

'The immune system comprises all the cells and tissues that protect us against pathogens, toxins and other foreign substances. Our first line of defence against attackers are the epithelial cells. These are in contact with the outside world, such as cells in the skin, lungs, intestines, etc.'

'The second line of defence consists of white blood cells. These are divided into an innate and an adaptive arm. The innate "phagocytes" are the first 'helpers' to arrive at the crime scene to identify the infection or damage and build up an initial defence. The cells of the adaptive immune system, on the other hand – the so-called T and B cells – are slower but work more specifically. They need time to adapt, multiply and learn to recognise and fight specific pathogens and cancer cells. They evolve with the disease, hence the name "adaptive".'

Phagocytes are the first helpers to arrive at the crime scene

'The immune system is everywhere in the body. White blood cells patrol not only the bloodstream but also the lymphatic system. The lymph nodes are like schools where ultra-specialised cells are trained. In each node, they guard a specific organ or area. The organs themselves also contain local, specific first responders: the resident macrophages."

When did biologists start noticing that cell death is not a random process at the edge of life, to be ignored, but a crucial part of life?  

Thus spoke Zarathustra

'We owe our interest in cell death to a tiny worm called C. elegans,' Peter Vandenabeele says. 'In the 1970s, Brenner, Sulston and Horvitz discovered that this roundworm loses exactly 131 of its body cells at predictable times. They reasoned that cells follow programmed genetic commands that activate a death mechanism in these 131 cells as part of the normal development of this worm.'

You have risen from worm to man, but much in you is still worm

'They also discovered the genes involved in the cell death process and were awarded the Nobel Prize for their work. So "death" turned out not to be an uncontrolled or random event after all. Mammals also inherited this cell death programme, and in that respect, we are not very different from worms – in line with what Nietzsche wrote in Thus Spoke Zarathustra: You have risen from worm to man, but much in you is still worm.'

'This programmed cell death was given the name apoptosis, the body's "neat" mechanism of cleaning itself. Phagocytes (white blood cells) quickly rush in to get rid of damaged or ageing cells by eating and digesting them ("phagocytosis"), and by recycling the cell's building blocks. 

Our immune system is not alerted in the process. There is no inflammatory reaction and we don't notice anything at all.' That is a good thing, because in the second you read this sentence, about a million cells in your body died through apoptosis. But neat apoptosis is not the only way of dying.

Blaring sirens, alarmines, smoke and debris

There are explosive forms of cell death too, like necroptosis and pyroptosis. The cell explodes and its contents leak into the intercellular space. 'That sets off a whole series of triggers,' Vandenabeele continues. 'The sirens start blaring. DAMPs (damage-associated molecular patterns) are released. These are proteins and pieces of RNA or DNA that are harmless within the cell, but are recognised as so-called alarm molecules ("alarmines") when they end up outside the cell. 

It's a bit like the debris and smoke after an explosion. The immune system registers the presence of these DAMPs and sends out the emergency services to clean up the mess.' Initially, this makes us ill or causes inflammation, but the aim is that our body heals. 'We are intensively researching necroptosis and its role in various illnesses, including cancer'

Does cell death happen when we get anthrax?

'Traces of Bacillus anthracis bacteria enter the bloodstream through food or inhalation', Alex says. 'Then the toxin begins to work, leading to anthrax. The anthrax toxin is recognised by certain sensors in the white blood cells and triggers cell death. But this happens on a massive scale, with white blood cells also dying, severely hampering the immune response.

What exactly happens has only been studied superficially and mainly in mouse models; little is known about human cell death mechanisms. Through my project, we want to explore this further and see whether pyroptosis, a special form of cell death, also plays a role and contributes to the excessive inflammatory response in humans. Without treatment, anthrax leads to organ failure and the person dies of sepsis or blood poisoning.'

Outsmarting death

Many other diseases can be traced back to disrupted cell death. Conditions such as autoimmune diseases and Alzheimer's are characterised by excessive cell death. 

With cancer, it's the other way around. Cancer reminds us of single-celled organisms that try to stay alive at all costs and outsmart death. They evade cell death and continue to divide unchecked. 'What's more, they mutate profusely, because cancer is in constant evolution. They switch off the mechanisms that activate cell death. They throw up a smokescreen. The immune system may sense danger, but it is left in the dark.'

Cancer cells switch off the mechanisms that activate cell death. They throw up a smokescreen

'Chemo- and radiotherapy cause cell death by stressing proliferating cells. However, these therapies do not yet target a single type of cell death; they go through our bodies with a broad brush and cause a mixture of cell death forms. Nevertheless, cancer cells usually die quietly, through apoptosis. That is not bad in itself, but the problem is that apoptosis does not stimulate the immune system, which is exactly what we want. Moreover, cancer treatment often also affects and paralyses the immune system. Just when we need it most.'

'That is why we are investigating whether we can encourage cancer cells to die via a type of cell death that sets off the alarm bells. We want the immune system to cooperate. Then it can closely monitor the mutations that occur during the course of the disease. 

The type of cell death is therefore decisive in treating the disease, especially in the longer term and when cancer comes back in a previously healed person. We also strive to target only cancer cells and not healthy cells, because that makes the patient ill. That is the double face of cell death. We want to promote cell death and avoid it at the same time, in a single organism.'

'However, there is no switch you can flip to achieve a certain result. The balance is delicate. By subtly adjusting a series of sliders, we want to push the system in a direction where the immune system actively cooperates. That is why we are investigating which processes trigger a fierce immune response. Let's take a look at viruses.'

Mimicking viruses

'When a cell is infected by a virus, necroptosis or pyroptosis often occurs. The cell dramatically sounds the alarm and triggers a cascade of reactions. The rescue workers of the adaptive immune system are massively called in. That is exactly what we want to mimic in cancer therapy: inducing cancer cells to undergo a dramatic form of cell death. We want them to die with a bang. 

We cells to die with a bang

Essentially, we want to make the cancer cells more "visible" to the immune system and keep the latter in a constant state of readiness. We call this phenomenon "viral mimicry". In an ideal scenario, we adjust a few sliders so that the cancer cell behaves as if it has been infected by a virus. It then proceeds to necroptosis.'

Messenger molecule

'One of the most powerful systems we have against viruses is a substance that acts like a messenger, called "interferon". When a virus enters a cell and inserts a piece of viral DNA or RNA, the cell starts to produce interferon. The sirens start blaring and the immune system springs into action. The cell's first response is to initiate cell death, sacrificing itself for the greater good, namely the protection of the entire organism. But the virus will first suppress that tendency. After a while, the virus then cleverly uses cell death to glide out of the cell and continue infecting.'

'But what is the parallel with cancer? Radiation or certain chemotherapeutic agents damage our DNA. Just like with a virus, pieces of DNA are released into the cell. Interferon is produced and necroptosis is initiated. That is what we want, because it stimulates the immune system.'

Fat's the question

Vandenabeele also cites another cell death pathway, the more recently discovered ferroptosis, which is controlled by metabolism rather than genes. It plays a role in Alzheimer's disease, heart attacks and organ transplants. 'An excess of oxygen, for example, oxidises in an iron-dependent way – therefore coined "ferroptosis" - the double layer of fat that surrounds each cell (the plasma membrane). This causes the contents to leak out and the cell to die.'

'Here's where it gets interesting: the cell's sensitivity to ferroptosis depends on the type of fat. Poly-unsaturated fatty acids (PUFAs) in the plasma membrane fall prey to ferroptosis, unlike mono-unsaturated fatty acids (MUFAs, e.g. olive oil) which have a protective effect. So, through your way of eating, you have access to a slider in the cell death system!' Here too, Vandenabeele and his team came across something striking.

Oxidizing cells?

'We are now investigating whether ferroptosis is an option for treating cancer when other cell death routes have been exhausted or in the event of a relapse or metastasis. Because what is the problem? Firstly, cancer cells resist apoptosis, necroptosis and pyroptosis – using the same antics that viruses initially use to delay cell death. Secondly, cancer cells become increasingly adept at evading cell death as the cancer progresses, evolves and mutates. Lung cancer cells, for example, can undergo up to thirty thousand mutations in a single human being! No wonder some mutations survive treatment and become more resilient. That is precisely why metastases are more difficult to treat.'

"Let cells die by oxidizing their plasma membrane?"

'It looks like ferroptosis may be a good alternative to other forms of cell death: you simply let cells die by oxidising their plasma membrane. That sounds great, but there is a catch. We recently discovered that ferroptosis does not strongly stimulate the immune system; the alarm bells remain (relatively) silent. 

And we want the opposite: a highly alert immune system. We are now doing a deep dive in this obstacle: we are actively looking for ways to trigger an immune response in ferroptosis. We have already achieved some promising results with PhD students Laura Wyckaert and Olivia Van der Sypt, among others.'

Treating metastatic cancer?

There is more hopeful news. 'Metastatic cells undergo an interesting evolution. The type of fat in the plasma membrane changes. This makes them more mobile, allowing them to spread. While doing that, their poly-unsaturated fat content (PUFA) increases. This works in our favour, because it makes them more susceptible to ferroptosis. We hope that ferroptosis can be a solution, especially in combination with an alerted immune system, particularly in the lungs, where there is a lot of oxygen favouring ferroptosis.'

'The overarching idea is to ensure that cancer cells always die in an immunogenic manner so that the immune system can act. This reduces the likelihood of the cancer returning. In our laboratory, we are also trying to find ways to target only cancer cells and not healthy cells. We do this by exploiting specific characteristics of cancer cells, particularly the mechanisms they use to protect themselves from cell death.'

'We are biologists and not medics', emphasises Peter Vandenabeele, 'however, on laboratory level, we are trying to stay one step ahead of cancer and other diseases through fundamental research.' 

It is clear that scientists no longer shy away from looking cell death in the face. Understanding the many faces of cell death – and the signals they send out – are indispensable links in better understanding the polyphony of our bodies and the connections between life and death.

Who is Peter Vandenabeele?

Peter Vandenabeele from Flanders, Belgium, is a world renowned expert in cell death. He is affiliated with the VIB (Flemish Institute for Biotechnology), Ghent University and the CRIG (Cancer Research Institute Ghent). He conducts fundamental, groundbreaking research into various forms of cell death, including necroptosis. He helped demonstrate that necroptosis is an actively regulated biological programme that occurs mainly in infections, inflammations and cancer. His work revealed that cancer cells that die via necroptosis trigger a strong immune response that can even act as an anti-tumour vaccine in mouse models. Vandenabeele's insights have changed our view of cell death and are essential for research into cancer, inflammatory diseases, infections and autoimmune diseases.

Kathelijne, editor of GondwanaTalks: I am intrigued by how earth, life, air, ocean and societies interact on geological and human timescales.

Why I started GondwanaTalks.

Donation?

An immense effort is poured into GondwanaTalks.

Are my articles somehow meaningful to you? Support my work so I can keep GondwanaTalks afloat. Your contribution makes an ultra-Plinian difference. Make a one-off or recurring donation and become a:

Stromboli Strategist
(€2/month)

Tambora Trailblazer
(€4/month)

Vesuvian Visionary
(€7/month)

Already donating? Thank you so much! Not a fan of paypal? Get in touch.

-----

Recent articles:

Do you like this post? Subscribe to the short newsletter: it is sent every couple of weeks when there is a new article, and is free of heavy files and irritating gifs.