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The NEI 40th Anniversary Symposia Series

Imaging the Dynamics of Embryonic Development

Scott E. Fraser

The explosion of progress in the fields of cell biology, biochemistry, and molecular biology has offered unprecedented knowledge of the components involved complex events such as embryonic development. The dramatic progress of these reductionistic approaches poses the challenge of integrating this knowledge of the building blocks into an understanding of the functioning system. Advanced imaging techniques offer an important stepping-stone between these disparate approaches, permitting us to spy on the assembly process and to pose questions about cellular and molecular events in the most relevant setting of the intact system.

Advances in light microscopy tools, such as confocal laser scanning microscopy (CLSM) and two-photon laser scanning microscopy (TPLSM), permit cells to be followed as they develop and migrate in the intact embryo. In vivo imaging of multiple labels should offer the ability to test proposed mechanisms by following different Green Fluorescent Protein color variants on multiple molecular species in the same cell.

However, there are two major stumbling blocks. First, image acquisition by laser-scanning confocal microscopy is often too slow to capture individual image planes with sufficient rapidity. Second, it is difficult to capture 4-D data at sufficient temporal resolution especially if there is any motion. When the studied motion is periodic, such as for a beating heart, a way to circumvent this problem is to acquire, successively, sets of 2D+time data at increasing depths and later rearrange them to recover a 3D+time sequence. Recently we have helped to develop a fast acquisition confocal microscope (Zeiss LSM 5 LIVE) that can acquire very rapid, high-resolution 2D optical sections of fluorescently labeled cells in the developing zebrafish heart. Together with this, we have established image registration algorithms allowing for the registration of periodic movements. This method has allowed us to create 4-dimensional working models of the heart and analyze mechanical forces related to wall and valve motions from different stages of heart development. This approach is generalizable to many different settings, ranging from developmental biology to neurobiology.

In parallel developments, we have developed a gene trap/protein trap strategy to create both functional fusions with endogenous proteins and conditional mutations. When combined with medium throughput imaging tools, these technologies offer a means to improve the rate at which imaging data can be acquired and processed, making it feasible to transform imaging into an –omics technique.

A new development is the refinement of biosensors with sufficient sensitivity to permit single cell proteomic experiments. The novel optical resonators make it possible to combine imaging studies of single cells with more quantitative analyses of protein levels and post-translational modifications.

Our hope is that the combination of faster and more sensitive imaging tools, optimized data collection and analysis approaches, and technologies for proteomic analysis at the single cell level, will offer new insights into the events that shape embryos and organs.

Scott E. Fraser

Scott E. Fraser, Ph.D.
Anna L Rosen Professor of Biology
Professor of Applied Physics
Professor of Bioengineering

Biological Imaging Center
Beckman Institute
California Institute of Technology

Scott Fraser has constructed and employed new imaging technologies to explore the inner workings of a wide variety of biological processes, in developmental biology, disease processes and stem cell biology. The ability of these imaging technologies to bring the analysis of biological events to intact cells in intact organisms has numerous applications to both biomedical research and clinical use. Products developed in his lab range from novel laser scanning microscopes to robust genetic testing devices.

Scott Fraser began his scientific career studying physics (BS in Physics, Harvey Mudd College, 1976) and biophysics (Ph.D. in Biophysics, Johns Hopkins University, 1979). In his 11 years at University of California, Irvine (Department of Physiology and Biophysics), he rose through the ranks to become Chairman. Fraser moved to Caltech in 1991 to become the Anna L. Rosen Professor of Biology and to found the Biological Imaging Center in the Beckman Institute. He has co-founded the Caltech Brain Imaging Center, which he directed until this year, the Kavli Nanoscience Institute, and the Rosen Center for Biological Engineering.

Department of Health and Human Services NIH, the National Institutes of Health