Integrated Biosciences co-founders Felix Wong, PhD, and Max Wilson, PhD, dream of making the most potent drug screen.
To do so, the biotechnology company has announced that it is teaming up with Illumina Ventures Labs to add single-cell transcriptomic profiling to its synthetic biology and AI-driven small-molecule drug discovery engine. The partnership will provide Integrated Biosciences with the resources, infrastructure, and raw sequencing power to generate transcriptomic atlases across hundreds of thousands of small molecules, figuring out how each molecule affects the RNA expression of a single cell.
“We’re doing the drug screen that I think can end all drug screens,” said Wilson. “Up until now, you could have done a series of different tests, asking single questions to get single answers iteratively until you found something, but each one of those assays has a unique and distinct transcriptional output. If we want to know what we need to drug, the information for that signature should be in our data as long as our library can move cells toward that phenotypic state.”
Imitating aging
In 2022, Wilson and Wong took their first step toward manifesting the ultimate drug screen, building a platform for decoding how small molecules affect the responses of cells to optogenetic perturbations driving disease-related phenotypes—work that was foundational for the founding of Integrated Biosciences.
Late last year, Wong, who was then a postdoc in the lab of James J. Collins, PhD, at MIT, showed that their platform could be used to identify novel classes of antimicrobials. But Wilson and Wong have pointed Integrated Biosciences in the direction of aging, to identify therapeutic strategies for age-related processes and diseases.
“Aging is really complicated—it’s a conundrum involving many different pathways,” said Wong. “But if you can actually tease out specific age-related pathways, then you can start to study them individually. We can leverage these optogenetic tools to isolate specific pathways, and we can then start to figure out how small molecules act on these very specific age-related pathways. Our synthetic biology tools allow us synthetic control of aging hallmarks.”
Wilson and Wong hope that adding the dimension of single-cell transcriptomics readouts will help them untangle aging and find combinations of small molecules that mimic the effects of known strategies that affect aging and age-related processes and diseases, such as parabiosis, exercise, or caloric restriction.
“If I ask you to develop a drug that mimics exercise, you might have specific targets, but in general, that’s a very hard problem,” said Wong. “We can, for instance, characterize the whole transcriptomic response to something like exercise. And then, given our atlas, basically pick out combinations of compounds that will mimic the response.”
Wong said Integrated Biosciences is building maps that involve treating old cells with human blood serum from young patients and then mapping the transcriptomic response, which they will try to mimic with small molecules.
An exercise in scale
This isn’t the first time small-molecule combos have been matched to cellular phenotypes, notably chemical reprogramming of cells to stem-like states. But Wong said that one thing that separates what Integrated Biosciences is doing from what others have done is that they are moving up several orders of magnitude in the number of molecules and perturbations, from the thousands to the hundreds of thousands.
“In this age of AI, data is king,” said Wong. “The fact that we can generate differentiated phenotypic screens is really what enables us to really pursue a partnership like this as opposed to if we were focused on a single target. One of the things that has limited something like this is just the scale. With this partnership with Illumina, we currently have the scale as well as the resources and raw sequencing power that’s actually needed to execute something like this. What we’re planning requires substantial investment, and we did have to invent new technologies to multiplex the sequencing at that level.”
Integrated Biosciences has other partners in the sequencing space, notably Fluent Biosciences, to optimize a scaled experimental protocol to screen hundreds of thousands of small molecules.
Wong also mentioned that he’d like to incorporate maps of epigenetic modifications, given that studies suggest links between methylation and aging—a controversial concept that Wong thinks this platform could help dissect.
“We’re building this foundational map for drug discovery and how each of many different small modules affects things like RNA, methylation, etc., with the idea that if you combine all of this information, eventually we’ll have a foundation model for drug discovery and everything we want to drug.”
Matter over mind
While Integrated Biosciences’ screening approach leverages AI, it doesn’t do so in a generative sense to create novel compounds.
“Everyone has been thinking about how we can fold better proteins or drug-specific proteins using new AI approaches,” said Wong. “This partnership highlights the novelty of Integrated Biosciences’ approach, which is developing new AI/ML approaches built on typical screens that leverage synthetic biology.”
Wong said that for a target-focused company, transcriptomics might be more of a validation experiment to show that any ligand or drug discovered does not screw cells up or alter cells in weird and unexpected ways.
“All I have to do now is do one experiment with a drug, understand how it changes the cell’s transcriptome, and then see how that transcriptome matches any of the possible transcriptomes we’re interested in,” said Wilson.
Though seemingly ripping at the seams with loads of potential, Integrated Biosciences is still a very early-stage company. The most significant output has been the publication of several papers on their methodology, and they have yet to show any evidence of naming any preclinical candidates, let alone clinical ones.
