“Digital Embryo” Created

How does a humble zygote grow into a fully functioning animal, billions or trillions of cells strong? This question has intrigued biologists for centuries. Now scientists have generated the first complete developmental blueprint of a vertebrate—a “digital embryo” mapping the positions, divisions, and movements of every cell during the first 24 hours of a zebrafish’s life.
“Such reconstruction of a complex vertebrate embryo had not been achieved before,” says Philipp Keller, a PhD candidate at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany. Keller is lead author of the paper, which appeared in the October 9, 2008 issue of Science.
Developmental biologists have long coveted such a tool, but imaging a complex organism’s growth presents a serious hurdle. After just one day, for example, a zebrafish already has 20,000 cells and a beating heart. To meet that challenge, Keller and his colleagues developed a new technique called digital scanned laser light sheet fluorescence microscopy (DSLM).
DSLM generated a three-dimensional image of the embryo by combining about 400 pictures taken along slightly different planes. The team repeated this process every 60 to 90 seconds, tracking changes as the zebrafish developed. In 24 hours, this amounted to about 400,000 images for each embryo.
To deal with this deluge of data—three terabytes per embryo—the researchers developed a computational pipeline. They wrote algorithms defining the structure of cell nuclei, then ran the microscopy data through a network of more than 1000 computers at EMBL and the Karlsruhe Institute of Technology in Germany.  
The computational analysis picked out every nucleus. Keller’s team then processed this information into comprehensive databases of cell positions, divisions, and migratory tracks. In all, they catalogued 55 million nucleus entries.
Digitizing the data was key. “Microscopy tells you about phenomena from a qualitative point of view,” Keller says. “But with digital embryos, we can count the number of cells that are involved in a process and see what they do.”
The digital embryo has many potential uses. For example, the researchers used it to determine that zebrafish germ layers—which eventually give rise to all of the fish’s tissues—form more synchronously across the embryo than previously thought.
Keller also envisions applications in tissue engineering and the study of tumor growth. Overlaying the digital embryo with genomic data also could be powerful, he adds. Researchers could learn which genes regulate vital developmental processes, such as organ formation. To encourage such progress in multiple fields, the researchers made their data public.
“This paper is groundbreaking,” said Kees Weijer, PhD, professor of developmental physiology at the University of Dundee in Scotland. “And making all the data available is very helpful since these coordinates will be used to compare the development of mutants.”



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