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Integrated Bio Developing Transcriptome, Methylation Screens for Small Molecule Drug Discovery


NEW YORK – Integrated Biosciences, a Bay Area startup with ties to the University of California, Santa Barbara, is planning to conduct ultra-high throughput gene expression and epigenetic sequencing to discover small molecule drugs.

The firm's approach involves a proprietary multiplexing scheme that will allow it to screen hundreds of thousands of candidate molecules, creating transcriptome and methylome profiles for each one.

"The novelty here is the scale of everything involved," said Felix Wong, a cofounder of Integrated Bio. "We had to invent many new molecular technologies to handle the scale, to index and process that many sequencing samples." Existing barcoding technologies are not able to handle the number of samples the firm needs at the cost it is willing to pay, he said. The company has also developed new data analysis techniques to match.

Though the firm's proof-of-concept work was done on specific pathways with mid-throughput sequencing, it is now moving to high-throughput, single-cell whole-transcriptome analysis using the method commercialized by Fluent BioSciences. The companies are collaborating to adapt Fluent's droplet emulsion technology with Integrated Bio's barcodes.

Integrated Bio has also joined the Illumina Ventures Labs program, the successor to the Illumina Accelerator. Wong and Max Wilson, a cofounder of Integrated Bio, are hoping that with access to high-throughput Illumina sequencing, they'll be able to find new small molecules or combinations of drugs that can be used to target stress response, which is implicated in aging-associated diseases such as cancer, diabetes, and neurodegeneration.

"Integrated Biosciences is an outlier early-stage company that has already pioneered breakthroughs in drug discovery," Illumina Ventures Partner Ron Mazumder said in a statement. "Illumina Ventures is convinced that, with our unique support and resources, Integrated Biosciences will unlock novel therapeutic candidates and modalities that bring next-generation sequencing to the forefront of drug discovery."

Founded in late 2022, Integrated Bio is one of several firms pursuing an idea called phenotypic drug discovery. "We're not drugging specific targets," Wong said. Data analysis is done phenomenologically, using artificial intelligence to learn what compounds have a particular phenotypic effect. "We'll have a response in terms of RNA transcripts and methylome modifications for a small molecule," he said.

The firm has licensed technology developed by Wilson at the University of California, Santa Barbara, which uses optogenetic modulation of molecular stress response.

With five full-time employees, it has recruited several star scientists to its advisory board, including chemistry Nobel laureate Dave MacMillan of Princeton University, where Wilson did his doctorate and postdoc; Jim Collins, a synthetic biology researcher at MIT and cofounder of Sherlock Biosciences; and Tim Lu, CEO and cofounder of Senti Biosciences, a synthetic biology-driven cancer therapeutics firm.

Wong said the firm raised a seed round of "a couple million dollars" but declined to provide specific figures. Investors include Root Ventures, Mission BioCapital, Conscience VC, Reinforced Ventures, and Polymath Capital.

The company is starting with a proprietary small molecule library of about half a million compounds. "Parts are from commercial sources, others we developed ourselves," Wong said, noting that it picked the library to optimize chemical diversity. This is to help make the initial survey as useful as possible, given that the universe of possible small molecules is enormous compared to what the firm will be able to assay. "If we do not find any hits, we might be able to train an algorithm to generalize" and suggest certain features that might be worth exploring further, Wong said.

As a starting point, Integrated Bio is working with fibroblasts and plans to construct an atlas of transcription and methylation profiles induced by its compound library.

The founders pointed to the Broad Institute's Library of Integrated Cellular Signatures (LINCS) for comparison, but said they plan to exceed its scale. Whereas LINCS will look at thousands of small molecules, Integrated Bio will look at hundreds of thousands. "If we tried to brute force something like this, we'd have to hire an army to run the screens and it would cost tens of millions [of dollars]," Wong said. 

To address the scale needed, Integrated Bio began working with Fluent earlier this year, which has also received funding from Illumina Ventures. That company's PIP-seq T20 kit can prepare 20,000 single cells per reaction, for approximately $.05 per cell. A 100,000 cell kit can get down to about $.03 per cell.

In an email, a Fluent spokesperson said the company is helping Integrated Bio "optimize their workflow on our smaller T20 kits before they move up to our larger T100 kits and beyond." Financial and other terms of the collaboration were not disclosed.

Integrated Bio hopes to have most of its atlas completed in the next several months, which could lead to a small molecule candidate, or even a combination of small molecules that show promise in modulating stress response.

"We're focused on aging, but we recognize there are a lot of interesting therapeutic opportunities," Wong said, suggesting they'll be open to collaborations where it will use its technology to investigate a different phenotype or transcriptomic response.

Integrated Bio is also working on methylation analysis, which is done via a separate assay. Current technologies for single-cell methylation analysis aren't available "at scale at a cost that's reasonable," Wong said, noting that the firm has a different way of looking at parts of the methylome, though he declined to disclose more. The company is also "exploring what additional information we can get as it relates to protein expression."