The coming together of two of the most transformative technologies of our age will shine a light on our understanding and manipulation of biological systems.
Earlier this year, we reported on Integrated Biosciences, a biotech combining synthetic biology and machine learning to target aging, and its collaboration with researchers at the University of California Santa Barbara. They 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.
This platform, which was featured on the cover of Cell Systems, triggers the ISR virtually using light and reveals how the accumulation of stress over time shifts a cell’s reaction from adaptation to apoptosis (programmed cell death) [1].
Longevity.Technology: Intrigued by the role of machine learning in deciphering complex cellular stress responses, we sat down with Max Wilson, PhD, the cofounder of Integrated Biosciences, to find out more about how this knowledge can be applied to develop innovative therapeutics and the role synthetic biology has to play in longevity.
Wilson begins by acknowledging here that biological aging ranks among one of the most complex processes conceivable.
“It is influenced by genetic, environmental, and stochastic factors and involves a variety of ‘pillars’ that interact in unknown ways,” he explains adding at the same time, biology has become such a data-rich science that machine models informed by this data are really the best tools for predicting outcomes.
The downfall of ML models, however, is that they are often not human interpretable; this means, explains Wilson, that their best application is when interpretation is not necessary.
“This can be when I just need predictions across a space over which I have training data or they can be used to generate interesting hypotheses for which intuition can later be developed,” says, adding that at Integrated, they take the second approach.
“We use graph neural networks to predict novel small molecules that will affect the activity of age-associated pathways, which are trained on data we generate in house using our synthetic biology approaches. We then take those putative longevity drugs and dissect their mechanism using a variety of techniques to build our intuition as to how and why the drugs work.”
Integrated Biosciences’ optogenetic tools can mimic the signaling state of an old cell, a diseased cell, or a young cell.
Cellular stress responses contribute to myriad age-related diseases, including neurodegeneration, cancer, diabetes and osteoarthritis. Integrated’s synthetic biology platform enables control over aging-associated stress response, and so far, the company has applied its basic SynBio approaches to senescence and the integrated stress response.
As well as operating over the set of different cellular stress responses, Integrated also operates over another dimension – the set of disease indications it hopes to use its novel compounds and platform to alleviate.
“To navigate this breadth, we are letting the science guide us, with an eye towards acute indications,” Wilson expounds. “The models of acute disease tend to be more predictive of human disease etiology and thus lower the risk of having the drug fail in clinical trials.”
Optogenetic tools may seem like a difficult concept to grasp, but Wilson explains it comes down to signaling.
The signal pathways that carry information from inside and outside of the cell do so in an inherently dynamical process – these signals have been observed to oscillate or pulse and can form waves or Turing patterns.
“It has become clear that the dynamics of these signaling pathways change as we age, potentially altering the information they carry or how cells decode that information,” explains Wilson. “Our optogenetic tools allow us to exactly specify the signals in these pathways by simply modulating the sequences of light that we shine on the cells. Therefore, we can mimic the signaling state of an old cell, a diseased cell, or a young cell.”
This ability to dynamically modulate signaling pathways in any way allows Integrated to recapitulate various aspects of the aging process that it then targets with small molecules.
“By finding small molecules that restore the aged signaling dynamics to youthful dynamics we can rejuvenate cells.”
In addition, Integrated Biosciences, is actively considering creating small molecules that can perform the cellular reprogramming, and the company has a SynBio platform for this in the works.
Synthetic biology is responsible for some pretty incredible tools that can program cells to execute a wide variety of both naturally occurring and even completely unnatural behaviors. Integrated is focused on using SynBio to perform unprecedented “on-pathway” screens for drugs that modulate age-related pathways. Wilson explains that the SynBio part of the platform ensures that the data the company uses in its ML models is of the highest quality and relevance.
So, is SynBio the future of longevity? If so, perhaps the future is already here, says Wilson, citing T-cell therapy, which is, he explains, really the first widely adopted application of SynBio, and adding that Integrated’s use of SynBio to discover new small molecules is another angle.
“Looking forward, I’m really excited for the applications of SynBio to other cell therapies in the longevity space,” says Wilson. “I’m hopeful for a future where a few engineered cells can be programmed to navigate to a specific part of the body and deliver rejuvenating factors locally, or even differentiate into new organs that can treat age related disease and regenerate tissue function.”
Dr Max Wilson is the cofounder of Integrated Biosciences
Wilson describes the merging of AI and SynBio is a narrative of convergence – two of the most transformative technologies of our age coming together.
“This synergy heralds a new era in biotechnology, where computational might intersects with the boundless potential of biology, driving innovations at a pace previously unimaginable.”
Integrated Biosciences is realizing the application of this convergence.
“We have a variety of lead compounds, borne from this synthesis of AI-driven insights and SynBio platforms, that we are preparing for IND-enabling studies,” explains Wilson. “Our aim isn’t just to drive innovation in isolation – we’re actively looking out for strategic partnerships with other pioneering biotech companies and VC firms.” Wilson adds that collaborative efforts like these can amplify the impact of discoveries, hastening their transition from the lab to real-world applications.
“In essence, the confluence of AI and SynBio is akin to the meeting of the mind and the maker,” says Wilson, adding that together, they promise not just incremental advances but leaps in our understanding and manipulation of biological systems.
“As they continue to feed into and amplify each other, we stand at the precipice of a renaissance in biotech, where the boundaries of what’s possible continually expand.”
[1] https://www.cell.com/cell-systems/fulltext/S2405-4712(23)00154-0
Photos courtesy of Integrated Biosciences / Max Wilson
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