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BioImage Informatics Conference 2017

Whole-animal imaging with high spatio-temporal resolution

Philipp J. Keller, Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA, USA

Light-sheet fluorescence microscopy has emerged as a powerful imaging method that provides exceptionally high imaging speed and high spatial resolution while minimizing the amount of light energy used to interrogate the specimen. This combination of capabilities makes light-sheet microscopy indispensable for developmental [1] and functional [2] in vivo imaging of complex biological systems with high spatio-temporal resolution.

We are developing advanced implementations of light-sheet microscopy, such as our SiMView [3,4], hs-SiMView [5] and IsoView [6] microscopes for simultaneous multi-view imaging of large living specimens, and are enhancing these instruments by adaptive imaging techniques for improving spatial resolution and automating complex imaging experiments [7]. We are using these methods to systematically reconstruct whole-embryo development in multiple model systems (fruit fly, zebrafish and mouse) at the single-cell level and to perform high-resolution functional imaging of the entire early nervous system.

Complementing these imaging techniques, we are developing strategies for automated, efficient and robust large-scale image processing of the resulting multi-terabyte light-sheet microscopy data sets [8], including methods for multi-view data processing, cell segmentation and cell tracking [9,10]. This combined experimental and computational framework allows us to quantitatively analyze neuronal activity across the nervous system of behaving animals, systematically extract developmental lineages and their interrelationships at the system level, and connect this developmental building plan to emerging functional properties of the nascent nervous system.


  1. P.J. Keller, “Imaging morphogenesis: technological advances and biological insights,” Science (2013)
  2. P.J. Keller and M.B. Ahrens, “Visualizing whole-brain activity and development at the single-cell level using light-sheet microscopy,” Neuron (2015)
  3. R. Tomer, K. Khairy, F. Amat and P.J. Keller, “Quantitative high-speed imaging of entire developing embryos with simultaneous multiview light-sheet microscopy,” Nature Methods (2012)
  4. M.B. Ahrens, M.B. Orger, D.N. Robson, J.M. Li and P.J. Keller, “Whole-brain functional imaging at cellular resolution using light-sheet microscopy,” Nature Methods (2013)
  5. W.C. Lemon, S.R. Pulver, B. Höckendorf, K. McDole, K. Branson, J. Freeman and P.J. Keller, “Whole-central nervous system functional imaging in larval Drosophila,” Nature Communications (2015)
  6. R.K. Chhetri, F. Amat, Y. Wan, B. Höckendorf, W.C. Lemon and P.J. Keller, “Whole-animal functional and developmental imaging with isotropic spatial resolution,” Nature Methods (2015)
  7. L.A. Royer, W.C. Lemon, R.K. Chhetri, Y. Wan, M. Coleman, E.W. Myers and P.J. Keller, “Adaptive light-sheet microscopy for long-term, high-resolution imaging in living organisms,” Nature Biotechnology (2016)
  8. F. Amat, B. Höckendorf, Y. Wan, W.C. Lemon, K. McDole and P.J. Keller, “Efficient processing and analysis of large-scale light-sheet microscopy data,” Nature Protocols (2015)
  9. F. Amat, W. Lemon, D.P. Mossing, K. McDole, Y. Wan, K. Branson, E.W. Myers and P.J. Keller, “Fast, accurate reconstruction of cell lineages from large-scale fluorescence microscopy data,” Nature Methods (2014)
  10. J. Stegmaier, F. Amat, W.C. Lemon, K. McDole, Y. Wan, G. Teodoro, R. Mikut and P.J. Keller, “Real-time three-dimensional cell segmentation in large-scale microscopy data of developing embryos,” Developmental Cell (2015)


Dr. Philipp Keller has been a group leader of Howard Hughes Medical Institute’s Janelia Research Campus since 2010.  After studying physics and computer science at the University of Karlsruhe and University Heidelberg, he pursued his Diploma Thesis and his PhD in biology at EMBL. As a graduate student working with Dr. Ernst Stelzer and Dr. Jochen Wittbrodt, he developed scanned light-sheet microscopy and performed the first systematic reconstruction of cell movements and divisions underlying the formation of an entire zebrafish embryo.  His “Digital Zebrafish Embryo” was named as one of the Top Ten Breakthroughs of the Year by Science and one of the Top Five Breakthroughs of the Year by The Times.

At Janelia, Dr. Keller is leading a highly interdisciplinary lab, in which optical physicists, computer scientists and biologists are working together to realize breakthroughs in microscopy and the imaging-based study of development and function of the nervous system. His lab developed SiMView, hs-SiMView and IsoView light-sheet microscopy technology, which allow whole-animal imaging in vertebrates and higher invertebrates with high temporal resolution and high spatial resolution simultaneously.  Over the course of the past five years, his laboratory published 40 peer-reviewed articles, including 10 publications in Science, Nature Methods and Nature Biotechnology,. These publications were selected five times for research highlights in Nature and Science, cited 1,400 times (Google Scholar, 1/17/17) and viewed online 200,000 times (NPG and AAAS, 1/17/17).