Current Research

Philipp Keller is interested in the principles underlying the developmental building plans of animals. He uses advanced light sheet microscopy and computational methods to quantitatively study embryonic and neural development in Drosophila and zebrafish.

Animal development is one of the most complex and impressive processes encountered in biology. In early embryonic development of vertebrates and higher invertebrates, a single cell is transformed into a fully functional organism comprising several tens of thousands of cells, which are arranged in tissues and organs able to perform the most spectacular tasks. Understanding development on a system-wide level is one of the most fundamental goals of biology. The ability to capture and characterize the dynamic behavior and state of all cells in a developing embryo will be an indispensable step toward this goal. The overall objective of our research is to gain such quantitative access in the most important animal model systems and to investigate the fundamental properties of their developmental building plans.

We are particularly interested in the principles characterizing early embryonic and late neural development. To elucidate these principles, we perform in vivo reconstructions and analyses of the patterns of cell migration and cell division, study the dynamic architecture of tissues and organs, and extract and computationally analyze the corresponding cell lineage trees. Our long-term goal is to uncover the fundamental, quantitative rules of development and to use these data for the establishment and validation of a morphogenetic model of development.

The tools required for comprehensive and quantitative studies of development in vertebrate and higher invertebrate species have become available only recently. Key technologies are high-performance light sheet–based fluorescence microscopes and highly automated approaches to computer vision.

We design and use advanced light sheet–based microscopes to record entire zebrafish and fruit fly embryos in vivo and with subcellular resolution. The light sheet concept employed in such microscopes provides fast three-dimensional imaging of large specimens at a high signal-to-noise ratio, while keeping photobleaching and phototoxic effects at a minimum. Owing to this combination of imaging properties, we can take full advantage of advanced fluorescent markers and simultaneously visualize cell movements, cell divisions, cell shape dynamics, and gene expression patterns in entire living embryos, for up to several days.

High-throughput approaches to image processing and data analysis complement the light microscopy and facilitate converting the image information of each recorded embryo into a digital representation. This step provides "digital embryos," which permit following cells and characterizing their state as a function of time, revealing both cell origin and cell fate. Genetic and morphogenetic information can be resolved at the same time and correlated on a system level. This approach allows us to reverse-engineer the developmental building plans of tissues and organs in a whole-embryo context and, thus, to analyze development of the entire organism systematically.

Currently, we focus on four topics. First, we reconstruct embryonic cell lineage trees from the developmental building plans and develop new computational methods to determine their characteristic properties. Comprehensive lineage reconstructions have so far only been possible in lower invertebrates, such as the nematode Caenorhabditis elegans, and thus, it is crucial to take the next step toward a better understanding of organisms with nonstereotypic development. Second, we use the digital reconstructions to study cell division patterns and tissue homeostasis. Oriented divisions are a powerful means to sculpt the embryo in the course of morphogenesis and also play an important role in the maintenance of tissue integrity. Third, we analyze the time course and coordination of cell movements and correlate this information to cell lineage decisions and the control of gene expression. This reveals important stages of differentiation and enables functional annotation of the building plans, e.g., by dissecting early signaling centers. Fourth, we study the development and architecture of neural tissues.

In all applications, we strive for quantitative understanding. The experimental analyses are therefore combined with biophysical modeling to reduce the results to simple rules that can be tested and validated by functional interference.

As of June 24, 2010

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