New Tool Maps Cellular Stress Memory

When does that seasonal tan turn into a melanoma risk? When might those extra pounds cause diabetes? Could severe head injuries cause Alzheimer’s to develop? In the grand scheme of things, genetics, lifestyle, and age are risk factors, with the solutions frequently appearing only after the unfortunate diagnoses.

However, a record of our physical slights, injuries, poor decisions, and abuses exists as stress at the cellular level. Investigators at UC Santa Barbara have discovered a way to map this cellular “stress memory landscape,” which analyses the stresses already experienced by cells and foretells how they will respond to new stresses in the future.

We’ve developed a platform that could allow us to eventually figure out how all stress-related diseases occur.”

Max Wilson, Study Senior Author and Molecular Biologist, University of California, Santa Barbara

The research appears on the cover of the journal Cell Systems.

In addition to deciphering the onset of cellular stress-related diseases, mapping out this landscape could result in measures that prevent or reduce the likelihood of those conditions, and more effective, innovative therapies.

What Does Not Kill Makes One Stronger

When the body’s cells are stressed, they mount a response to bring things back into balance. The integrated stress response (ISR) is a complex signaling pathway that can be ignited from both inside and outside the cell by stressors like trauma, toxins, or pathological conditions.

“Stress will elicit a response that will either help the cells to adapt, or kill them, if the damage is too great,” Wilson noted. When the stress is low-level and infrequent, the response is typically transient. When stress is consistent or severe enough, the responses can direct to chronic diseases such as diabetes, neurodegeneration, or cancer.

The ISR keeps a record of cellular stresses and responses to these stresses, which the researchers investigated by inducing “virtual stress,” or activating the ISR to produce a response without actually damaging the cell.

The researchers activated this ancient, evolutionarily conserved signaling pathway shared by all eukaryotes (organisms with cells that have nuclei) by shining light on light-responsive proteins in their platform, allowing them to communicate “hack into human stress signaling networks,” Wilson said.

Unlike other ISR-inducing substances like chemicals and physical stimuli, light makes it easy to observe these responses.

It can be complicated to determine the response from pure stress because the response can be conflated with the damage caused by the stress-inducing poison, or trauma.”

Max Wilson, Study Senior Author and Molecular Biologist, University of California, Santa Barbara

Other cascading failures caused by toxins or physical damage, and also cellular repair processes, can obscure observations of how the ISR chooses which genes to activate in response to stress. The optogenetic method used by the investigators also allows for precise control over the intensity, duration, and frequency of the virtual stress.

According to the research, “the difference between an adaptive and a maladaptive stress response is commonly defined by the differences in dosage and timing of a stress input.” They discovered that cellular stress memory is made up of the combination of previous stress and recovery time following the stress.

The ability to control the integrated stress response in various ways and to different degrees provides insight into a number of cellular stress-related conditions linked to the ISR. These response signals are impacted by aging, which has been linked to adult-onset diabetes and neurodegenerative diseases like Huntington’s disease.

Cancers may also be caused by faulty translation of healthy signals into oncogenic ones, resulting in uncontrolled tumor growth. Manipulation of cellular stress memories may also become possible in neurodegenerative diseases caused by a failure to forget or remember past cellular stresses, like ALS and vanishing white matter disease.