New synthetic biology platform with novel optogenetic technique enables control over aging-associated stress response.
Integrated Biosciences, a biotech combining synthetic biology and machine learning to target aging, in collaboration with researchers at the University of California Santa Barbara, today announced a drug discovery platform that enables precise control of the integrated stress response (ISR), a biological pathway that is activated by cells in response to a wide variety of pathological and aging-associated conditions.
A new publication, Optogenetic control of the integrated stress response reveals proportional encoding and the stress memory landscape, authored by company founders and featured on the cover of Cell Systems, describes a technique that triggers the ISR virtually using light and demonstrates how the accumulation of stress over time shifts a cell’s reaction from adaptation to apoptosis (programmed cell death) .
“In a very real way, our platform puts cells into a virtual reality, making them experience stress in the absence of physical stressors,” said Maxwell Wilson, PhD, a cofounder of Integrated Biosciences and Assistant Professor of Molecular, Cellular, and Developmental Biology at the University of California Santa Barbara.
“This work is an important advance because it relies on a light-activated switch to control the ISR, which is key to aging, rather than using the chemical poisons that are common in this field of research. Our synthetic biology platform enables previously impossible drug discovery because it avoids inducing the collateral damage caused by chemical poisons, enabling us to observe direct effects of drug candidates on the cell’s stress response and perform fast and accurate target deconvolution.”
Longevity.Technology: Integrated Biosciences’ ‘cellular virtual reality’ system adapts optogenetics, a research method pioneered by neuroscientists to activate specific neurons by wiring them to fire in response to flashes of light – lightspeed longevity, if you will.
The Integrated Biosciences’ platform used neuroglioma and osteosarcoma cancer cells that had been genetically modified so that their ISR would respond to light. The research found that duration and intensity dictate how a cell reacts to the VR stress, and also that the accumulation of stress over time plays an important role in how the cell responds.
Transient stress leads to an adaptive response that protects a cell from damage, but prolonged activation of the ISR leads to cell death. As the ISR represents a key hallmark of aging, these findings inform the cell fate decisions that cells make as they age.
The Cell Systems paper represents the second major publication associated with Integrated Biosciences. A Nature Aging paper, Discovering small-molecule senolytics with deep neural networks, published in May, demonstrated how AI can be used to discover novel senolytics, antiaging compounds that selectively eliminate senescent “zombie” cells. These compounds have shown promise in their ability to treat age-related diseases such as fibrosis, neurodegeneration and cancer, but have faced challenges in clinical studies. The Nature Aging paper identified three drug candidates that have comparable efficacy and superior medicinal chemistry properties than those of the most promising senolytics currently under investigation .
By combining cutting-edge technologies described in these two publications – AI-driven small-molecule drug discovery and precise synthetic control of aging-associated pathways – Integrated Biosciences is aiming to generate significant and unprecedented types of data regarding the activities and properties of their antiaging drug candidates – data that should substantially derisk future clinical trials that target age-related diseases.
“This study demonstrates an important pillar of Integrated Biosciences’ platform – that the company can use synthetic biology, and in particular optogenetics, to control age-related cellular signaling pathways. 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,” said James J Collins, PhD, Termeer Professor of Medical Engineering and Science at MIT and founding chair of the Integrated Biosciences Scientific Advisory Board.
Synthetic biology is has rather taken off in the past decade, in part due to pioneers such as Integrated Biosciences’ founding SAB Chair Jim Collins.
To find out more, Longevity.Technology reached out to Integrated Biosciences cofounder Maxwell Wilson, PhD. He explained that a key premise of synthetic biology is the re-imagining of cells as computing units.
“This is a powerful analogy that reframes the problem of disease as an information processing defect and the development of therapies as a programming challenge,” he explained, added that Integrated Biosciences envisions a future where therapies can precisely modulate the information processing capabilities of cellular pathways that degrade with age and age-related diseases.
“In this future, we may simply reprogram cells into functioning properly, as they once did. We founded Integrated Biosciences to address this grand challenge using synthetic biology, AI, and small molecules. We’re unique in taking this type of approach: our founding and advisory teams include the strongest scientists in the world in all these areas of research, and our highly supportive investors have told us that we’re an entirely differentiated company in their portfolios.”
Wilson explained that Integrated Biosciences’ application of synthetic biology, and in particular cellular optogenetics, allows it to overcome a central challenge in drug discovery.
“Even if we had complete knowledge about how signaling patterns direct cell behavior, until now, we’ve been largely incapable of mimicking the complexity of the signals cells experience in vivo,” Wilson told Longevity.Technology. “Thus, we have been unable to find drugs that restore these complex signals back to healthy baselines. Importantly, this applies to alterations in signaling that cells experience as they age, which is associated with reduced signaling speed and low-levels of basal signaling activity in many pathways. The usage of optogenetics allows us to recapitulate key signalling pathways without taking dirtier approaches, like using toxic small molecules to induce aging stress responses. In addition, light-based control of biology is a new modality that is scalable and highly reconfigurable. These features allow us to probe the complex dynamics of aging in high-throughput for drug screens.”
And that is not the end of the story. As the name suggests, Integrated Biosciences has many core programs that use different, state-of-the-art approaches from synthetic biology, AI and small molecules. To expand on that, Wilson refers to a major program that leverages Integrated Biosciences’ cellular optogenetic tools to virtually modulate cellular signaling pathways (stress signaling, developmental signaling, immune signaling, &c) and develop advanced, pathway-specific screening platforms, in which the biology can be controlled in a clean and dynamical manner using light.
“We’ve also been utilizing the on-pathway, disease-modifying compounds found in these screens to develop graph neural networks that allow us to mine and generate billions of compounds in silico. This combination of synthetic biology to tame complex biology and AI to model new chemistry enables us to find first-in-class drugs that re-wire diseased cells,” said Wilson.
We’ll be diving into Integrated Biosciences in greater depth in an interview with cofounder Maxwell Wilson, PhD – stay tuned!
Photos courtesy of Integrated Biosciences