BBS Faculty Member - Sean Megason

Sean Megason

Department of Systems Biology

Harvard Medical School
200 Longwood Ave, WAB 536
Boston, MA 02115
Tel: 617-432-7441
Fax: 617-432-5012
Email: megason@hms.harvard.edu
Visit my lab page here.



Embryonic development is the execution of a program encoded in the genome. The Megason Lab has initiated a project called the Digital Fish Project to decompile this program comprehensively. We ultimately wish to upload zebrafish development into a computer so we can quantitatively understand how the genome computes the formation of an embryo from an egg. We combine confocal/2-photon imaging of living zebrafish embryos with genetics, genomics, synthetic biology, and computational analysis to watch biological circuits function in vivo and use these data in cell-based, quantitative modeling.

Our approach to doing systems biology in embryos is heavily based on imaging because of its unique ability to capture quantitative, longitudinal data at single cell resolution in a living, functioning system. We use zebrafish because of their unique suitability for imaging, genetics, and genomics. We are developing a technology called “in toto imaging” that seeks to track all the cells in a developing tissue and extract quantitative, cell-based data through the use of fluorescent reporters. For in toto imaging we label all the cells in the embryo with a “segmentation marker” that allows the cells to be tracked; we then capture 3d time-lapse movies of their development on confocal and custom built 2-photon microscopes; and finally use a software package we are developing called GoFigure to track all the cells. In toto imaging will allow us to determine complete lineages for organs and to extract cell-based frameworks for use in modeling. We are currently employing in toto imaging to determine the complete lineage of the inner ear and spinal cord and wish to apply this approach to the entire embryo in the future.

We are also developing a technology called FlipTraps. FlipTraps are a novel kind of gene trap with 2 important features: they generate endogenously expressed functional fluorescent fusion proteins, and they generate Cre conditional alleles. Fluorescent fusion proteins are very useful because they allow us to non-invasively quantitate expression and localization of proteins in vivo. FlipTraps also provide the first approach to generating Cre alleles outside of mice or yeast allowing us to knockout gene expression in a very specific fashion. By combining FlipTraps with in toto imaging, we can digitize expression and phenotype with single cell resolution for use in molecular and cellular based modeling of developmental processes.

We are currently scaling up these efforts as part of the Digital Fish Project which aims to scan in protein expression and mutant phenotype systematically onto a cell-based armature of the zebrafish and to use these data to construct models that “compute” developmental processes.



Last Update: 8/22/2013



Publications

For a complete listing of publications click here.

 


 

Megason SG, Fraser SE. (2007). Imaging in Systems Biology. Cell, 130:784-795. pdf

Gouaillard A, Brown T, Bronner-Fraser M, Fraser SE, Megason SG. (2007). GoFigure and The Digital Fish Project: Open tools and open data for an imaging based approach to system biology. Insight Journal

Megason SG, Fraser SE. (2003) Digitizing life at the level of the cell: high-performance laser-scanning microscopy and image analysis for in toto imaging of development. Mech Dev. 2003 Nov;120(11):1407-20.

Megason SG, McMahon AP. (2002) A mitogen gradient of dorsal midline Wnts organizes growth in the CNS. Development. 2002 May;129(9):2087-98.



© 2013 by the President and Fellows of Harvard College