How to Turn Single-Cell Data Into a New Class of Cell-Depleting Therapies

Why treating the cell, not the protein, could turn chronic disease treatment into something closer to a cure. You've built single-cell pipelines that spit out clusters, p-values and target lists, but nothing that survives contact with the clinic. What if the clustering method itself is quietly leading you astray? Adam Freund is Founder and CEO of Arda Therapeutics, a biotech using single-cell sequencing to find the pathogenic cells driving chronic disease. He spent seven years as a Principal Investigator at Calico Life Sciences, building a research lab on the biology of ageing and helping grow the company from 15 to more than 200 people, and holds a PhD in Molecular and Cell Biology from UC Berkeley. You'll get a working model for how Arda's discovery engine turns single-cell and spatial transcriptomic data into causal cell targets. Adam explains why a common statistical shortcut in single-cell analysis produces disease signals that don't hold up and how cell depletion could replace daily dosing with a handful of treatments that reset the immune system. Ross and Adam cover how Arda finds pathogenic cell populations across hundreds of donors, why chi-squared tests on cell clusters can substitute cell count for donor count without anyone noticing, and how B-cell depletion therapies proved that removing a cell can beat blocking its pathway. This one is for data science leaders and computational biologists building single-cell pipelines, not listeners after a general intro to drug discovery. Key Takeaways - Chi-squared tests on cell clusters draw their statistical power from the number of cells, not the number of donors, so a single oversampled patient can produce the same p-value as a hundred-donor study. - Rituximab clears 100% of B cells from circulation yet does nothing for lupus because the disease-driving cells live in tissue, not blood, a lesson now shaping where Arda tests its own molecules. - Neighborhood analysis scores each cell by the donor identity of its nearest neighbours rather than forcing cells into predefined clusters, producing a continuous disease-enrichment map with no cluster boundaries. - When depleted cells regrow, they often come back without the trait that made them harmful in the first place, which means a handful of doses can hold a chronic disease in remission for months. Chapter Markers 00:00 Why cell depletion beats pathway blocking 01:05 Welcome Adam Freund to the show 01:30 From Calico Life Sciences to founding Arda 03:29 Why blocking one pathway rarely works 05:32 B-cell depletion as the proof of concept 08:14 Building a modular library of depletion tools 10:46 Single-cell sequencing removes the need for a hypothesis 11:43 Why clustering is a dial, not ground truth 15:24 The chi-squared trap in single-cell analysis 20:40 Neighbourhood analysis and donor-weighted scoring 23:44 Moving from enrichment to causality 26:32 Inside Arda's lead fibrosis program 30:33 Why solid tissue testing beats blood samples 34:25 Simulating depletion in spatial transcriptomic data 38:49 The case for intermittent dosing over daily pills 43:58 The data infrastructure behind Arda's platform 48:46 Where spatial and protein data are heading Useful Links & Resources - Adam Freund on LinkedIn: https://www.linkedin.com/in/adam-freund-0657654 - CorrDyn: https://corrdyn.com Connect With the Show - Host Ross Katz on LinkedIn: https://www.linkedin.com/in/b-ross-katz/ - Host Ross Katz on X: https://x.com/brosskatz - CorrDyn on LinkedIn: https://www.linkedin.com/company/corrdyn/ If your team runs single-cell pipelines, how do you currently decide on the number of clusters, and have you ever checked whether your significance scales with donor count rather than cell count? Tell us in the comments; we're building a running list of data QA checks for biotech data science teams. Visit corrdyn.com to learn how CorrDyn can help your organization extract value from data.