Rong Fan：Ushering in a New Era of Human Biology

The human body is an extraordinarily complex, dynamic, and heterogeneous multi-cellular system, which cannot be fully recapitulated by any model organism. As the saying goes, “mice get models, humans get disease.” Gaining a deep understanding of human molecular biology has long been a challenge, largely due to the limited ability to investigate biological mechanisms directly within human tissue specimens – especially those archived in clinical tissue banks worldwide. Over the past decade, spatial transcriptomics, enabled by imaging or sequencing-based approaches, has emerged as a powerful tool to map molecular and cellular landscapes and genome-wide gene expression profiles within intact tissues. However, these technologies have yet to integrate additional omics layers needed to reveal deeper biological mechanisms and to achieve full compatibility with clinically archived tissue samples. Our laboratory pioneered “spatial multi-omics” by achieving the first spatially resolved co-mapping of whole transcriptome and hundreds of proteins (Liu Y, et al., Cell, 2020), the first demonstration of “spatial epigenomics” sequencing (Deng Y, et al., Nature, 2022; Deng Y, et al., Science, 2022), as well as spatial co-profiling of epigenome and transcriptome on the same tissue sections (Zhang D, et al., Nature, 2023). However, formalin-fixed paraffin-embedded (FFPE) tissue blocks – the most abundant human biospecimens stored in clinical biobanks – have remained largely incompatible with spatial omics assays. This represents a critical unmet need and a major barrier to unlocking the full potential of human biology research and translational development. We recently developed Patho-DBiT – a first-of-its-kind platform for spatially resolved profiling of diverse RNA species – including microRNA, tRNA, snoRNA, lncRNA, region-specific RNA splicing isoforms, as well as genome-wide single-nucleotide RNA variants to decode cancer evolutionary dynamics in each patient’s tumor and reveal underlying epigenetic mechanisms – all from routinely archived clinical FFPE specimens (Bai Z, et al., Cell, 2024). Human clinical trials represent the most biologically relevant experiments for studying human biology. However, until recently, their utility in directly uncovering biological mechanisms with both depth and breadth from clinical biospecimens has been limited. This is now changing! Building upon efforts to develop virtual cell large-language models that capture the fundamental principles of molecular cell biology, spatial multi-omics technologies – including those pioneered in our laboratory – are poised to connect such models with spatial omics data. Together, they offer unprecedented power to decode the complexity of human biology and guide the design of personalized treatments, ushering in a new era of human biology research and precision health.

Rong Fan, is the Harold Hodgkinson Professor of Biomedical Engineering and of Pathology at Yale University. He earned his Ph.D. in Chemistry from the University of California, Berkeley, and completed postdoctoral training at the California Institute of Technology before joining Yale University’s faculty in 2010. Dr. Fan’s research focuses on developing single-cell and spatial omics technologies to investigate functional cellular heterogeneity and intercellular signaling networks in human health and disease. He is a co-founder of IsoPlexis, Singleron Biotechnologies, and AtlasXomics and has served on the Scientific Advisory Board of Bio-Techne. His contributions have been recognized with numerous awards, including the National Cancer Institute’s Howard Temin Career Transition Award, the NSF CAREER Award, and the Packard Fellowship for Science and Engineering. He is an elected fellow of the American Institute for Medical and Biological Engineering (AIMBE), the Connecticut Academy of Science and Engineering (CASE), and the National Academy of Inventors (NAI).