Integrated Biosciences’ optogenetics platform illuminates aging pathways in cells

Integrated Biosciences’ optogenetics platform illuminates aging pathways in cells

Atrial fibrillation. Parkinson’s. Retina degeneration. Optogenetics, a technique that uses light to alter gene expression and thereby control cell activity, is gaining traction both in research and as a potential therapy. Now, scientists have found another possible use for it: drug discovery, specifically for age-driven disease.

In a study published July 19 in Cell Systems, researchers from Integrated Biology and the University of California, Santa Barbara described how they used optogenetics to simulate the integrated stress response (ISR)—signaling pathways activated in response to cell stress and implicated in aging—in synthetic cells. This allowed them to create a controlled environment through which they could see accumulated stress leads to cell death without the need for external stressors that could confound results.

“In a very real way, our platform puts cells into a virtual reality, making them experience stress in the absence of physical stressors,” Maxwell Wilson, Ph.D., co-founder of Integrated Biosciences, said in a press release.

The ISR is a signaling network found in virtually all eukaryotic cells. When a cell is, say, infected with a virus or deprived of glucose, the ISR might be activated. This could take the form of upregulating certain genes or slowing protein synthesis in an attempt to return the cell to homeostasis. Under excessive stress, it could also mean the cell self-destructs.

Scientists sometimes study cellular response by using external stressors—think viruses, synthetic RNA or physical harm like heat shock—to induce the ISR. The problem with this approach, from Integrated Biosciences’ point of view, is that it can have “pleiotropic effects,” or impacts beyond the ones that were intended. That can make it difficult to ascertain cause and effect. For instance, are the observed changes the result of the cell’s machinery failing, or do they stem from a cellular stress response?

An ideal approach for teasing out variables and outcomes in the ISR would have three properties, the researchers explained in their study. First, it would isolate an individual stress sensor and activate it virtually, so the scientists could focus on a single pathway and see how it impacts the cell. Second, it would allow for “high resolution” control over the stress sensor, meaning they could control precisely how much and how frequently the sensor is activated.

Finally, the researchers needed to be able to control the stimulation dynamics of the stress sensor—that is, controlling how the stress sensor responds over time, making it possible to see how past stressors change the ISR.

To that end, the team developed an optogenetics platform that allowed them to remotely control a single type of enzyme, PKR, found within the ISR pathway. This “selective activation,” as the researchers put it, didn’t have the unwanted side effect of off-target damage, streamlining the upregulated signals that were turned on as a result. Changing the intensity of the light altered the number of activated kinases and, thus, the intensity of the stress response.

Quick aside: Of all the enzymes to choose from the ISR, why PKR? The kinase is responsible for detecting markers of cell stress, like viral or endogenous double-stranded RNA, and plays an important role in maintaining homeostasis within the cell. It’s also known to be dysregulated in cancer and neurodegenerative disorders, the researchers noted in their paper.

“Thus, the interrogation of [the ISR] through optical control of PRK has both a broad significance and specific implications for understanding the fundamental mechanisms cells use to respond to stress,” the scientists wrote.

The team validated its platform on neuroglioma and osteosarcoma cells, taking time-lapse images of them as they continuously stimulated them with light. The results showed that both the duration and the intensity of the light could alter signaling in the ISR. The scientists also saw that, despite activating the stress pathways for more than 16 hours, there were no signs that the cells were undergoing apoptosis, or programmed cell death. Possible explanations included that the cancer cells had reconfigured their stress response to become immortal, that additional types of stimulation were needed to actually kill off the cells or that 16 hours simply wasn’t enough time to induce self-destruction, the scientists reasoned.

“Studies of how the ISR is re-wired across a range of cancers using orthogonally-controlled stress sensors such as ours could reveal how oncogenic transformation selects for … states that curb ISR-induced cell death,” they wrote.

Now that they have a way to control the ISR, the researchers plan to pair their platform with artificial intelligence to identify drug candidates that can alter cell stress pathways. In a paper published in May in Nature Aging, Integrated Biosciences showed how its AI platform could identify anti-aging drugs that eliminated senescent cells, a hallmark of aging. Ultimately, the hope is that by combining the optogenetic platform with AI, the researchers will be able to identify new treatments for age-related disease and de-risk clinical trials.

“This technology allows for novel drug discovery efforts, allowing us to query specific aspects of cellular biology that produce faster, on-target drug screens with built-in mechanism of action validation,” James Collins, Ph.D., founding chair of Integrated Biosciences’ scientific advisory board, stated in the press release.

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