Autophagy: The Incredible, Edible Cell?

Autophagy: The Incredible, Edible Cell?

True, weird fact: our cells are cannibals. Right now, these itty-bitty sacs of vital fluids inside your body are eating themselves. This phenomenon is called autophagy, or “self-eating.”

This seemingly odd phenomenon is old news to biologists. They already know that autophagy is really about cellular cleanup and recycling, not cannibalism. It’s a highly regulated process by which cells disassemble unnecessary or broken bits into their component building blocks. Our bodies then use what used to be junk to make new parts.

Alas, like many bodily functions, autophagy sometimes run amok. Scientists have implicated problems with the process in a range of health issues including neurodegeneration, cardiac disorders and cancer. That’s bad news for those of us with bodies.

The good news is that biotech firms have noticed that out-of-whack autophagy can wreak havoc on our bodies.  Many are now working on interventions that activate or inhibit autophagy. The efforts may yield new approaches to disease and illness.

Cellular Recycling & Reuse

Autophagy occurs continuously at low levels in most cells. Here’s what happens: damaged or defective cell parts such as proteins, lipids, and even entire substructures (organelles) such as mitochondria, the energy-providing “powerhouses” of the cell, are enclosed in lipid vesicles – bubble-like containers composed of the same material as the cell membrane. The loaded vesicles then fuse with an organelle, called a lysosome, which has an acidic pH and contains digestive enzymes. The lysosome works somewhat like a stomach—its caustic “juice” breaks down cellular junk into its constituent bits. The “cellular stomach” then releases these back into the cell to form new components. Autophagy thus serves two purposes: “cleaning out” old or defective parts, and providing new building blocks.

Autophagy can also be also induced by cellular stress. Sometimes the stress arises from nutrient deficiencies. Sometimes it comes from a lack of oxygen (ischemic injury), infection, or the presence of damaged proteins or organelles.

Cellular Cannibals & The Brain

Scientists suspect that autophagy protects our brains by flushing out toxic proteins that accumulate in disorders like Huntington’s disease, Alzheimer’s disease and Parkinson’s disease.

Defects in autophagy have been associated with the aggregation of mutant huntingtin proteins in Huntington’s disease and with the buildup of amyloid-beta plaques in Alzheimer’s disease. And in Parkinson’s disease (PD), defects in mitophagy are commonly associated with inherited types of PD. “Mitophagy” refers to autophagy directed at mitochondria – an important process for keeping these energy-producing factories healthy enough to fuel neuron function.

Cancer’s Foe; Cancer’s Friend

Autophagy is a double-edged sword when it comes to cancer. It helps suppress tumor formation thanks to its ability to protect cells from stress. However, if a tumor does end up developing, autophagy may end up feeding the tumor’s cells, instead of the body’s. In fact, most tumor cells display increased rates of autophagy.

Cardiac Health

Heart attack blocks oxygen flow to the heart, resulting in tissue death. Recent studies show that increased autophagy can help minimize this damage. Abnormal autophagy has also been associated with other problems including muscular problems, liver disease, and inflammatory disorders.

In The Pipeline

Biotech companies have begun to look at ways of harnessing the powers of autophagy for good. Let’s take a look at some of the possibilities:

• Casma Therapeutics (Cambridge, MA) was launched earlier this year to find ways to boost autophagy to treat a range of diseases. The company is now conducting clinical trials in muscle disorders, liver disease, inflammatory disorders, and neurodegeneration.
• PhoreMost (Cambridge, U.K.), in collaboration with the University of Cambridge, is conducting preclinical studies to identify drug targets to increase autophagy in neurodegenerative disorders.
• Phase II clinical studies are currently being conducted on Novartis’ (Basel, Switzerland) cancer drug Tasigna as a treatment for Parkinson’s and Alzheimer’s disease. Originally approved to treat chronic myelogenous leukemia, the drug works by inhibiting an enzyme that promotes cell division. Tasigna also blocks a protein that interferes with the function of lysosomes. Obstructing their function decreases autophagy.  Relieving the inhibition should increase autophagy.In 2015, a small Phase I study of Tasigna in Parkinson’s patients showed significant improvement in these patient’s symptoms. A new, Phase II study will demonstrate whether these promising results hold true for a larger group of patients.

Autophagy promises to be an important mechanism for a range of different therapeutic areas. These are still early days in translating these findings from the lab to the clinic, but stay tuned – this complex story has only just begun.