News and Publications

Year In Review - 2000

Cell Biology

Sandra L. Schmid, Ph.D., Chairman

hile human genome sequencing has provided a list of all cell components, their functions are still largely unknown. Answering these questions will drive research in cell biology well into the new millennium. The recently acquired genetic blueprint provides a foundation for the new discipline of functional genomics, a mining expedition that goes into the depths of cell biology to link an individual's genetic organization with their physiology. The Department of Cell Biology is uniquely positioned to exploit the vast information base of the human genome. Using sophisticated tools, its scientists are placing newly identified genes within their functional context. Understanding the operation of the living cell will help create new therapeutic approaches to treating cancer, heart, lung, muscle, and retinal and neurodegenerative disease.

Drs. Velia Fowler, Bill Balch, Sandy Schmid and Larry Gerace are teasing apart the complex biological processes that govern cell motility, the biosynthesis of essential cellular proteins, the uptake of essential nutrients and hormones, and communication between the nucleus (where the genome is stored and where gene expression is initiated) and the cytoplasm (where the protein products of the genome are synthesized). Fowler's work on muscle cell development provides insight into cardiac disease and muscular dystrophy. Cystic fibrosis is a disease caused by the aberrant synthesis and intracellular transport of a protein essential for maintaining fluid balance in the lungs. By identifying and characterizing the cellular machinery and processing pathways, Balch's work is aimed at providing more effective avenues for its treatment. Schmid has discovered that a protein associated with membrane dynamics at the cell surface may function as a cellular gatekeeper, ready to respond to invasion or disruption of the cell's membrane barrier. This protein may provide a new target for eradicating cancer cells.

Accessing the huge amounts of information in the genome is aided by knowing the functional context in which each gene product is expressed. John Yates, Ph.D., a recent recruit to the department, is a pioneer in this new area of research called proteomics. His laboratory has developed sophisticated tools and computer programs that enable the detection of protein differences between normal cells and cancer cells, allowing identification of a potential weakness that can be targeted by therapy. Categorizing proteins in functional sets is a valuable approach to mining the human genome.

To view the dynamics of living cells and the machinery within, Klaus Hahn, Ph.D., has developed innovative chemical biosensors that can be attached to proteins. When the protein is switched on or after a specific biochemical reaction, the biosensors emit a fluorescent light that can be easily followed with a microscope and a digital movie camera. In a related effort, Clare Waterman-Storer, Ph.D., has created fluorescent-tagged molecules that emit light as they assemble themselves into larger cellular machines. With these new methodologies, researchers can now watch cells respond to intercellular signaling in real time, and follow these events within living cells -- the same environment in which all genes and proteins interact. These techniques could provide the basis for high through-put screens to identify drugs that block metastasis of cancer cells, or the infiltration of blood cells leading to cardiac disease.

TAKING ADVANTAGE OF THE GROWING KNOWLEDGE OF THE GENOME

A comprehensive understanding of how proteins function requires knowledge of their structure. Crystallography and NMR structural analysis yield structural information on individual proteins or small protein complexes, but cellular machines are often composed of multiple proteins inaccessible to conventional structural analysis. The department has assembled a world-renowned center employing electron microscopy to create high-resolution structural images of large molecular complexes. Using these techniques, Ron Milligan, Ph.D., has examined the tiny motors that cause muscles to contract, and has unveiled the elegant means by which they generate force and movement. Mark Yeager, M.D., Ph.D., has solved the structures of viruses revealing their susceptibility to intervention, and the structure of cardiac GAP junctions that coordinate heart beats.

In the human body, specialized cells work together to govern physiology. Steve Kay, Ph.D., studies the effect of biological clocks and the proteins that make them run. Recently, he discovered that these clocks operate on the cellular level. Clock components actually perceive light, so that daily activities are coordinated with sunrise and sunset. Ben Cravatt, Ph.D., has identified a new class of signaling molecules generated in the brain that control sleep and other brain activities. Others in the department, including Shelley Halpain, Ph.D., and new recruits, Drs. Ardem Patapoutian and Mark Mayford, are dissecting the nervous system to discover how we learn and how our sense of touch develops.

The breadth and depth of the department is a tribute to the pioneering leadership of its late Chairman, Norton B. Gilula, Ph.D. Using and developing new investigative tools that range from proteomics, to the biochemistry and structure of complex cellular machines, to high resolution images that let researchers observe in-cell dynamics in real time, cell biologists are poised to take advantage of our growing knowledge of the genome. In the coming years they will better understand the machinery and mechanisms governing the complex cellular processes essential for life and their role in health and disease.