The technology needed to answer questions like those was not available commercially, Cheng said, so he and a team of engineers, physicists, data scientists and biologists set out to develop the technique themselves.

After a decade of optimizing the sample preparation and imaging, the team created 3D reconstructions of young zebrafish that can be examined from the whole organism down to a cellular level. Zebrafish were chosen to develop this technology because their size from larvae to adults is nearly the same as samples used by physicians to evaluate cancerous tumors.


According to Cheng, researchers and clinicians can now examine features like 3D shape, volume, location and number of cells that previously couldn't be studied using traditional histology. The technique will allow pathologists to study a full tissue sample after it has been stained and prepared. It is no longer necessary to cut a single slice of tissue out of the entire sample.

Clinical scientists can evaluate microscopic and three-dimensional features of cells due to the increased clarity and resolution of the images.

"The beauty and complexity of the tissue I saw was mind-bending," Cheng said of the images released in the journal eLife with the research on June 11.

Computational tools combined with the imaging allow the size, shape, volume and density of cells to be calculated and cataloged. This ability enables the characteristics of disease pathology to be studied in a novel way that may improve clinical care and facilitate drug discovery.

Advances in computer technology allow the large image files of the zebrafish - at 100 gigabytes each - to be processed and viewed. Researchers can examine the traits of disease at the organ system, tissue or cellular level simultaneously, slice-by-slice or in 3D context. They may even be able to see and interact with the cellular structure of organisms using the same technology used by virtual reality gamers.

Future research by the Cheng team aims to increase the resolution, sample size, throughput, analytical power and accessibility of the technique.

Other researchers from Penn State College of Medicine include Yifu Ding, Daniel Vanselow, Maksim Yakovlev, Spencer Katz, Alex Lin, Xuying Xin, Jean Copper, Victor Canfield, and assistant professors of pathology Khai Chung Ang and Damian van Rossum.

Also working on the project were Darin Clark, now at Duke University Medical Center; Phillip Vargas, University of Chicago; Yuxin Wang, Omnivision Technologies; and Xianghui Xiao and Francesco De Carlo, Argonne National Laboratory.

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