Brain, heart, and liver diseases are caused by loss of cells, but a tsunami of insights into how cells die is providing the first treatments and lifestyle changes for deadly, intractable diseases

Alzheimer’s disease, ALS, and Parkinson’s disease. Stroke, MS, and heart attack. These are the big, deadly diseases we can’t cure, and can hardly treat. They all involve untimely and mysterious deaths of cells that are the building blocks of critical bodily organs.

But a rapidly expanding field of cell biology is revealing how these cells die, how they can be protected, and ways these diseases might be cured with medicines and diet. Already hints of cures are emerging as new findings overturn centuries of misunderstanding.

For hundreds of years, scientists believed that cells just wear out, falling apart over time, like a favorite T-shirt. Biology doesn’t work that way — cells are carefully regulated, and if you can discern the inner workings of cells, you gain control over them.

In the 1990s, researchers discovered a form of cell death, termed?apoptosis, regulated by specific genes. Eliminate these genes and the cells turn into zombies–never fully dying, but never disappearing. This study showed that you can save cells even at the very end of their life by taking away a key gene they need to die. Death is not automatic or predestined, at least for our cells. If you take out cell death genes before the cells are damaged, you can entirely protect them, preserving their normal, healthy state.

The discovery of apoptosis was disappointing in some ways — many diseases in which cells are lost don’t involve apoptosis, but something else. Researchers once again assumed that other than apoptosis, cells just fall apart in deadly diseases.

Many ways a cell can die

In the last two decades, other major types of cell death were discovered, as well as some minor types. Now, huge progress is being made at unraveling the molecular details of how these forms of cell death operate. Excitingly, these are the mechanisms by which cells die in many diseases — the previous dark matter of cell death and disease.

With mechanistic insight come therapeutic options. The burgeoning knowledge of how cells die is leading to new drug targets and drug discovery strategies for saving cells that would otherwise die in degenerative diseases. Reading the cell death program is providing researchers the ability to recode the program.

• Necroptosis?is a form of cell death involving cell membrane pores and is implicated in gut problems, such as inflammatory bowel disease, as well as the damage caused by heart attacks. Removing one of the genes, appropriately named RIPK3, needed for heart cells to die by necroptosis protects the heart. Drugs that block necroptosis are advancing through clinical trials.

• Pyroptosis?occurs during many infections, leading to runaway inflammation. Drugs that block pyroptosis are also in the works.

• Ferroptosis?was discovered in my lab in 2012 and in parallel genetic studies by Marcus Conrad, PhD, at Helmholtz Munich. Ferroptosis causes iron-dependent damage to cell membranes, and is involved in degenerative diseases, including Alzheimer’s and ALS. Indeed, one of the genes,?iPLA2beta, mutated in Parkinson’s Disease patients is needed to prevent ferroptosis. When this gene is lost in these patients, some brain cells undergo ferroptosis, leading to Parkinson’s.

Ferroptosis is intriguing, because new?research?shows it is intimately connected to diet and metabolism. It may be possible to create diets that prevent ferroptosis, and prevent degenerative diseases driven by this type of cell death.

From mechanism to medicine

Creating new medicines takes tremendous time and resources. But once we know why a problem in the body happens — the mechanism — we can often create a suitable treatment.

The landscape of cell death is providing the mechanistic substrate for drug discovery.

Excited about the possibilities of this field, I recently wrote a comprehensive?review (PDF)?for the scientific journal?Nature Reviews Drug Discovery?with Kamyar Hadian, PhD, at Helmholtz Munich.

In the review, we provided “a roadmap for the emerging landscape of controlling cell death for therapeutic gain, which we expect to be a rapidly growing sector of the pharmaceutical and biotechnology industries.”

Creating new medicines in the modern era means identifying a specific gene or protein that must be blocked by a drug. Each type of cell death has revealed exciting new drug targets:

• RIPK1, RIPK3, and MLKL?are key proteins that execute necroptosis. Removing the genes encoding these proteins or blocking these proteins with drugs prevents cells from dying this way.

• NLRP3 and caspase-1?are the major drivers of pyroptosis — take away these proteins, and cells undergoing pyroptosis are rescued.

• Lipid peroxides?are damaged molecules that drive ferroptosis. Blocking the formation of these lethal lipids protects cells from dying through ferroptosis.

Pyroptosis causes the memory deficits in at least one mouse model of Alzheimer’s Disease. In this model, the driver of pyroptosis,?NLRP3, gets turned on, leading to brain inflammation.

However, removing the pyroptosis genes?NLRP3?and?caspase-1?from Alzheimer’s mice prevents memory loss.

Also, pyroptosis of brain cells called microglia releases factors that cause aggregation of amyloid beta, a driver of Alzheimer’s. Preventing the release of these dangerous factors from microglia undergoing pyroptosis protects mouse brains.

These studies are in mice, but as summarized in the review, drugs targeting pyroptosis, as well as necroptosis and ferroptosis are moving into clinical development.

On the cusp of serious breakthroughs

The bottom line is that we are on the cusp of finally being able to control whether cells live or die, pulling the levers of cell mortality when and how we choose. These new forms of cell death together fall under the heading of?regulated necrosis. It increasingly appears that all death is regulated, either by apoptosis or one of the forms of regulated necrosis.

Ten years ago, we did an intriguing experiment in my lab. We put together a cocktail of all the known cell death blockers we could find — 27 of them. When we treated cells in a dish with this cocktail, we couldn’t find any drugs that would kill the cells. The cocktail made them immortal — impervious to otherwise lethal treatments.

That long-ago experiment gave me hope that if we could map the complete set of death pathways, we could find a way to block each and every one of them, and prevent diseases driven by cell death. That hope is beginning to blossom into reality, and I am optimistic that cracking the riddle of how cells die is on the horizon, and ultimately the key to creating healthier ways to live.