The microscopy developed by Philipp Keller and colleagues has the potential to give scientists a systems-level understanding of how cells behave and interact during development.

This detailed way of watching development in action is the result of the latest version of the light-sheet microscope, developed by a team of scientists at the European Molecular Biology Laboratory

(EMBL) in Heidelberg, Germany. The new tool has the potential, says team member Philipp Keller, now a fellow at HHMI’s Janelia Farm Research Campus, to achieve a goal coveted by developmental biologists: the generation of comprehensive computer models of embryogenesis in complex vertebrates.

Before this innovation, Keller notes that scientists had been able to reconstruct, in a comprehensive way, the development of only simple animals such as Caenorhabditis elegans—a tiny worm that hatches when it reaches just 500 to 600 cells, within 12 hours after fertilization.

100 minutes after fertilization, a zebrafish has 64 cells, arranged in a seemingly random pattern. But over the next 24 hours, they morph into deliberate shapes. By the end of the first day of development, the embryo is in the Phyrangula stage, characterized by the emergence of a beating heart. Watch the transformation here.

Scientists studying the zebrafish, which grows to tens of thousands of cells on day one of its three-day embryonic development, had captured images of the embryo’s transformation into a juvenile. But they could describe the stages of development only in broad strokes. They had no tool to explore in detail the mysteries of gene expression, morphogenesis, and cell movement and division patterns. Existing microscopes often damaged embryos.

In addition, the strategy of patching together multiple images from different specimens left sizable holes in the resulting information. Part of the problem is that every embryo develops slightly differently. “If you stitch together data from different animals,” says Keller, “you don’t get the same coherent data set that you’d get by looking at one animal and observing it over time. Live microscopy was the only option.”

But in the early 2000s, microscopes fell short of the task.

“Neither confocal nor two-photon microscopes were fast enough,” says Keller. “The limitations in imaging speed do not allow following cell behavior for the entire organism, and, in the confocal microscope, the fluorescent markers would bleach very quickly and the embryo would be alive only for a short time.”

Photo: Paul Fetters
Video: Philipp J. Keller, EMBL Heidelberg

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