Reviewed by Lexie CornerMar 12 2025
Researchers at UT Southwestern Medical Center have developed a new “self-driving” microscope that addresses two major challenges in microscopy: imaging living cells or organisms at radically different scales and tracking a specific structure or area of interest over extended periods. This innovation is already enabling observations that traditional techniques have not been able to achieve.
The “self-driving” microscope developed by UT Southwestern scientists enables imaging and analysis across scales – from imaging an entire organism (top) to imaging immune-cancer cells' interaction with sub-cellular resolution (below and right). Image Credit: UT Southwestern Medical Center
Our work demonstrates a significant advancement in integrated bioimaging, enabling long-term observation of biological dynamics across scales from cellular to systemic levels to ultimately better understand developmental and disease processes.
Reto Fiolka, Ph.D., Associate Professor, Lyda Hill Department of Bioinformatics and Cell Biology, UT Southwestern Medical Center
Dr. Fiolka and Dr. Stephan Daetwyler, an instructor in the Lyda Hill Department of Bioinformatics, co-led the development of the new microscope.
Dr. Daetwyler explained that light-sheet microscopy has been used by scientists for the past 20 years to make numerous biological discoveries. This technique involves tagging specific structures in a sample with fluorescent probes, which are then excited by a thin plane of light. These probes emit light in response, allowing researchers to easily locate and capture images of the tagged structures, helping to understand their functions in health and disease.
However, Dr. Daetwyler pointed out a major limitation of light-sheet microscopy: the smaller the area imaged, the higher the resolution. This required scientists to decide, before starting an experiment, which resolution and field of view to use. As a result, they could either capture a few cells with high resolution or image a whole living organism at low resolution. Dr. Daetwyler noted that this restriction has made it difficult to fully understand biological processes, as most occur at the cellular, tissue, and organismal levels.
Drs. Fiolka and Daetwyler, along with their colleagues, addressed this challenge by combining two types of hardware: axially swept light-sheet microscopy (ASLM), developed at UTSW in 2015, which provides high-resolution imaging, and multidirectional selective plane illumination microscopy (mSPIM), a technique for low-resolution imaging.
The team also developed custom microscope hardware control software that allows users to switch between these two modalities in less than a second.
Dr. Fiolka noted that another challenge with light-sheet microscopy is tracking structures over time. He explained that many biological processes are dynamic. When studying processes that take place over hours or days, it is often necessary to manually adjust the microscope's field of view as organisms and cells grow, move, and multiply.
To address this issue, the researchers integrated a tracking mode into the new microscope's control software, enabling it to "self-drive." This feature allows the microscope to continuously track a specific region of interest over extended periods, such as hours or days, with users defining the region during the initial setup.
The researchers used zebrafish larvae, which are transparent and only a few millimeters long, as a biological model to image human cancer cells injected into them. These larvae are commonly used in cancer research.
They observed that immune cells called macrophages were able to easily target and eliminate osteosarcoma cells, a type of bone cancer. However, despite close interaction with the immune cells, skin cancer cells were not eliminated. Upon examining the macrophages, the team noted shape changes that aligned with their biological functions at various stages.
For example, the shape of circulating macrophages differed from those involved in the immune response.
Drs. Daetwyler and Fiolka mentioned that several colleagues at UTSW are already using the new platform in their research. Since the microscope's control software is open source, researchers can modify it to meet their specific needs.
A broader understanding of biological processes across scales will impact our knowledge about many diseases. This includes cancer progression, metastasis, developmental disorders, systemic diseases, and cardiovascular diseases, to name just a few.
Dr. Stephan Daetwyler, Lyda Hill Department of Bioinformatics and Cell Biology, UT Southwestern Medical Center
Additional authors of the study include Danuser, Ph.D., Chair and Professor of the Lyda Hill Department of Bioinformatics; Rolf Brekken, Ph.D., Professor of Surgery at the Hamon Center for Therapeutic Oncology Research, and Professor of Pharmacology; Felix Zhou, Ph.D., and Dagan Segal, Ph.D., Instructors in the Lyda Hill Department of Bioinformatics.
Co-authors include Jill Westcott, Ph.D., Research Scientist; Hanieh Mazloom-Farsibaf, Ph.D., and Bingying Chen, Ph.D., Postdoctoral Researchers.
Dr. Fiolka is also a member of the Harold C. Simmons Comprehensive Cancer Center.
The study was supported by the Swiss National Science Foundation, the National Institute of General Medical Sciences, and the National Cancer Institute.
Journal Reference:
Daetwyler, S., et al. (2025) Imaging of cellular dynamics from a whole organism to subcellular scale with self-driving, multiscale microscopy. Nature Methods. doi.org/10.1038/s41592-025-02598-2.