The Cheng lab is interested in fundamental genetic and molecular mechanisms that cause cancer, basic mechanisms underlying the relationship between human skin pigmentation and cancer, and contributing to web-based infrastructures for science, education, and public service. Our laboratory pioneered genetic screens in zebrafish to find new genes related to cancer. Our screens targeted two processes affected in cancer: mutation and cell differentiation. We are producing an on-line, high-resolution, full-lifespan atlas of the zebrafish that will be integrated with other anatomical web sites of zebrafish, other model organisms, and other disciplines. Collaboratively, we are developing 2D and 3D image informatics tools for systems biology and medicine, and new methods for X-ray based high resolution 3D imaging at cellular and subcellular resolutions.
We have collected human genetic samples from many unique populations and use a number of bioinformatic approaches to analyze and explore SNPs, whole genome sequences, and structural variation. To model candidate changes in zebrafish, we use molecular genetic techniques such as CRISPR/Cas9 editing, morpholino antisense oligonucleotide knockdown, humanized zebrafish orthologous rescue (HuZOR), and Tol2 transgenesis to elucidate relationships between genotype and phenotype. Through this strategy, we discovered a major genetic component of human European skin color through the corresponding zebrafish mutant, golden (Lamason, Cheng et al., 2005, Science).
Zebrafish as a Human Disease Model
The Zebrafish Functional Genomics Core at Penn State College of Medicine was established to provide the Penn State research community with a modern, centralized facility for housing, breeding and performing experiments with zebrafish, one of the fastest growing model systems in biomedical research, as well as the intellectual infrastructure to do that work.
The foundations of our research lie in two-dimensional (2D) histology. In addition to the 3D tools we are developing, we also have the latest slide scanner and software from Aperio to allow for 2D imaging and analysis. We work with collaborators in and outside of Penn State to develop new ways to look at and analyze these large (~50GB) slide scans. As part of the Department of Pathology, we are interested in learning how digital imaging and analysis can help pathologists better understand human disease.
We use a custom micro-CT setup, designed and built by our MD/PHD student Yifu Ding, to perform whole-organism phenotyping at histological resolutions in 3D. Some organisms we have imaged include zebrafish, drosphilia, and daphnia; we have also imaged human samples obtained from pathological biopsy. We use this imaging method with a sophisticated data processing pipeline to systematically analyze phenotype, of which we have recently published (Ding et al., 2019, eLife). The overall goal of this project is to achieve high-throughput phenotyping (through imaging and analysis) to enable phenomics. As gene sequencing and gene manipulation tools improve, our goal is to develop a unbiased, whole-organism screening tool that can coordinate with the wealth of genetic data.
Our understanding of European skin is already partially delineated: in 2005, our lab uncovered one of the most pervasive genetic mutations (SLC24A5) that contribute to the light color of European skin. Europeans also carry a 10 to 20-fold increase in melanoma susceptibility (one of the deadliest forms of skin cancer) when compared to Africans. Surprisingly, East Asians, unlike Europeans, carry a seemingly unusual protection against melanoma: their incidences of disease are similar to those of Africans, despite their relatively light skin color due to yet unknown genetic pathways.
To understand this, the first step is to identify these East Asian-specific genetic mutations.
Skin Color project link
Micro-Computed Tomography (micro-CT) is rapidly becoming commonplace in biological applications where the generation of high resolution, isotropic, 3D datasets is useful for both qualitative and quantitative phenotyping as well as visualization. While there is a fairly wide selection of commercial micro-CT scanners, optimization of sample preparation and scanning parameters can require a larger and more specialized setup than what is readily available. The focus of the Cheng lab Wide Field Micro-CT Project is to construct and continuously develop a system that optimizes high (cellular) resolution while maintaining a large field of few.
As of late 2018 the scanner is fully operational, with the majority of remaining work now focused on optimizing field of view and image quality through various customizations in reconstruction techniques and hardware. Currently we are testing scintillators of various thicknesses and materials, improving sample drift correction, and experimenting with scan times to improve resolution, reconstruction quality, and signal to noise ratio. We are most excited about our most recent development, a 10,000 by 7,000 pixel resolution camera that improves our field of view five-fold, allowing us to fit centimeter-scale samples into a single scan. We intend for our developmental micro-CT rig to serve as a financially-viable framework for labs interested in research-oriented CT imaging as well as an easily translatable setup for improved image acquisition at more powerful synchrotron sources.
Micro-CT project link
Contact: Dan Vanselow, Max Yakovlev, Yifu Ding.
The atlas project was originally focused on the microanatomy of zebrafish and humans, viewable as virtual slides at www.zfatlas.psu.edu. The content is being re-organized to have subsections devoted to zebrafish, humans, mice, and other model systems. We are working on ways to present micro-CT-based 3D histology. We welcome ideas and high-resolution slides and images from the community and are seeking collaborations that would make the resource more valuable.
The Bio-Atlas is organized with subsections devoted to humans, zebrafish, mice, and other model systems. The project was originally focused on the microanatomy of zebrafish. To address the need for a more human orientation, we introduce the Bio-Atlas as a platform for coordination of data between human and other model systems.
Since pathophysiological mechanisms in humans are reflected in tissue architecture, morphological changes in the best models of human disease will involve similar phenotypes as in humans. We welcome ideas and high-resolution 2D and 3D images from the community and are seeking collaborations to expand this resource.
The Cheng lab is collaborating with syGlass, a cutting edge scientifically-oriented Virtual Reality platform, which aims to greatly simplify the process of visualizing and manipulating high-resolution micro-CT data while making that data available to scientists and the general public.
"High resolution polygon meshes, 4D movies, and volumetric imaging data can be ingested quickly and easily, producing immersive VR renderings that provide new insight into data of all shapes and sizes." -syGlass
Try out the Cheng Lab's latest 3D datasets at syGlass.io