The Development and Applications of Multimodal Interferometric Imaging to Measure Nanoscale Structure and Macromolecular Motion


Chromatin, a complex nuclear structure comprised of DNA, histones, RNA, and other nuclear proteins, is one of the most critical components within the cell because it houses the genetic information and its organization regulates important cellular functions, such as transcription, replication, and repair. Its structural organization is well understood at the nucleosomal (<20-nm) and chromosomal (>200-nm) levels; however, due to the lack of nanoscale quantitative imaging modalities, little is known about the higher-order structure and dynamics between those length scales. Here we present recent advances in the development of Partial Wave Spectroscopic (PWS) microscopy extending the technique into a multimodal label-free interferometric imaging platform for measuring intracellular nanoscale structure and macromolecular dynamics in living cells with a sensitivity to macromolecules as small as 20nm and millisecond temporal resolution. This system has been applied in vitro to explore changes in higher-order chromatin structure and dynamics that occur due to a variety of biological processes, such as cellular fixation, stem cell differentiation, and ultraviolet (UV) light irradiation. Through this exploration, we discovered a new phenomenon, cellular paroxysms, a near-instantaneous burst of motion that occurs during UV induced cell death. Additionally, multiple medical applications were explored such as detecting colorectal cancer early, determining colorectal cancer surveillance timelines, and aiding in the development of cancer therapeutics. Given this platform’s ability to obtain nanoscale sensitive, millisecond resolved information within live cells without concerns of photobleaching, it has the potential to answer a broad range of critical biological questions about macromolecular behavior in live cells, particularly about the relationship between cellular structure and function.

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