A novel optogenetic screening platform enables control over previously intractable biological systems. Using the screening platform, scientists have been able to selectively activate the integrated stress response (ISR). The platform enables a high-throughput screen of 370,830 compounds.
In turn, they discovered several ISR-potentiating compounds that sensitize stressed cells to apoptosis without inducing cytotoxicity across diverse cell types and stressors—an elusive therapeutic profile not achievable with traditional ISR drugs in development. More specifically, the study reveals that “these compounds upregulate activating transcription factor 4 (ATF4), sensitizing cells to stress and apoptosis, and identify GCN2 as a molecular target.” They also showed broad-spectrum antiviral activity in vitro, and one compound significantly reduced disease pathology and viral titers in a mouse model of ocular herpesvirus infection.
This work is published in Cell in the paper, “Optogenetics-enabled discovery of integrated stress response modulators.”
The platform was developed by scientists at Integrated Biosciences—a Redwood City-based biotechnology company integrating optogenetics, chemistry, and AI to discover small molecule therapeutics for age-related diseases.
By integrating programmable, light-responsive domains with automated high-throughput screens, the platform interrogates biological systems with millisecond temporal precision and micron-scale spatial resolution. This modular system allows researchers to resolve compound effects in real time, across diverse targets, cell types, and disease-relevant contexts, providing a level of precision and control not achievable with conventional screening technologies.
“Synthetic biology tools like optogenetics allow us to precisely tune complex cellular processes, something traditional drug screening cannot do,” said Maxwell Wilson, PhD, co-founder and CSO of Integrated Biosciences. “Our platform lets us activate specific targets and pathways with light, generating clean, interpretable readouts and the discovery of high-precision compounds, often with unprecedented mechanisms of action, that were previously inaccessible.”
The platform enables selective, pathway-specific activation without the off-target or systemic confounding effects. This is especially critical in phenotypic screening and AI-driven discovery, where data quality remains a major bottleneck to extracting meaningful insights.
Beyond the ISR, Integrated Biosciences’ optogenetic platform offers a generalizable strategy for discovering small molecules that modulate complex, traditionally hard-to-drug targets and pathways, including those central to aging. Because the system is modular and tunable, it can be rapidly adapted to explore a wide range of biological processes with on-pathway, on-phenotype precision.
“This is only the first demonstration of what our optogenetic platform can do,” said Wilson. “Synthetic biology gives us the control we need to build more accurate, disease-relevant discovery systems. Our goal is to bring this level of precision to other pathways where conventional tools have failed.”
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