Department of Cell Biology

Researchers in the Department of Cell Biology work on a range of problems, from the most basic (the structures of single molecules and how they function), to the most complex (the integration of populations of cells into tissues, whole organisms, and their complex behavior). They seek to apply their mechanistic understanding of these biological processes to the search for new therapies and diagnostics for such ailments as heart, lung, muscle, retinal, and neurodegenerative diseases, and cancer.

Cell structures interact with one another in a dynamic way, and investigators take a multi-tiered approach to understanding the basic mechanisms behind these interactions, combining the sophisticated tools of molecular and structural biology, chemistry, and genetics with those of traditional cell biology. Researchers in the department are developing and employing tools to watch molecular events in living cells in real time--and in the actual environments in which all genes and proteins interact. One technique involves attaching innovative fluorescent chemical dyes to proteins that reveal molecular signaling events that would otherwise be impossible to see, like events that control cell migration in living cells. These dyes fluoresce in response to specific biochemical events, like changes in protein conformation, protein binding, or post-translational modifications, allowing scientists to determine when and where in the cell they occur.

TSRI scientists have also developed methods to watch the dynamics of assembly and disassembly of microfilaments and microtubules, which together constitute the cytoskeleton upon which all cell movement is based. This technique, called fluorescence speckle microscopy, uses a fluorescence microscope and video camera to follow the dynamics of tiny amounts of fluorescently labeled assembly units as they become incorporated into growing cytoskeletal elements at one location or are removed at another.In essence, one can watch cells "flex" their cytoskeletal muscles to learn how cells move, change shape, and divide.

Another powerful imaging technique used by cell biologists at TSRI is electron microscopy, which can produce three-dimensional maps of the large molecular assemblies of the cell. Few proteins work alone in the cell; most function as part of larger molecular machines--machines like the transcription complexes that make messages from the genes, membrane channels and pumps that import and export materials, and tiny motors that cause muscles to contract. While static, high-resolution images of the individual protein components of these machines can be obtained by x-ray crystallography, electron microscopy enables researchers to visualize the whole machine and its operation under physiological conditions. Maps of the machines at different stages of their work cycle can be calculated from electron images and combined with the x-ray crystallographic data to yield a detailed description of the structure and action of the entire machine.

While many cells stay put as part of a tissue, other cells move, for example to fight an infection, to generate new blood vessels after injury or, in the case of cancer cells, to mount their invasion of the body. In addition to understanding the intracellular machinery mediating movement, researchers in the department are dissecting the signals and identifying the cellular and secreted proteins that direct and regulate cell movement to control such processes such as wound repair, angiogenesis, and metastasis.

Often the regulation of protein activity is controlled through post-translational modification and/or by protein interactions. Members of the department have developed sophisticated tools and computer programs to detect these subtle protein differences and to identify the interactions. They hope that by comparing these complex patterns of regulation in normal cells with those in dysregulated cells associated with diseases like cancer, they will identify potential weaknesses that can be targeted by drug therapy.

Other investigators are working to identify molecules involved in vesicle formation and trafficking through the cell. One research group has discovered a new enzyme belonging to the serine/threonine kinase family and has provided evidence that the enzyme regulates the uptake of essential nutrients into the cell. Another group is identifying and characterizing the cellular machinery and processing pathways for CFTR, a protein essential for maintaining fluid balance in the lungs. The devastating childhood disease cystic fibrosis is caused by the aberrant synthesis and intracellular transport of CFTR and investigators hope to provide more effective avenues for treatment of this disease.

While we experience pain or heat or cold, these are sensed at the cellular level. One group has characterized an important enzyme that modulates pain sensation. Our brains release a compound called anandamide, which provides some natural pain relief by binding to receptors on neurons in the pain-modulating center of the brain. However, this effect is weak and short-lived as other molecules, particularly an enzyme called fatty acid amide hydrolase (FAAH), break down the anandamide. FAAH may be an excellent target for pain therapy not only because it breaks down the natural molecules that provide pain relief but also because it seems to be the only enzyme responsible for doing so. The recently solved three-dimensional structure of FAAH may help in the development of new drugs to control pain. Another group has identified the receptor responsible for sensing "cold." Interestingly, this same "cold" receptor responds to menthol, explaining the "cool refreshing" burst we feel as we eat a breath mint.

Another investigator identified and isolated a protein, called TRPM8, that mediates the body's ability to sense cold and menthol through the skin. TRPM8 is the first cold-sensing molecule that has ever been identified and may be an important basic target for pain-modulating drugs. Also identified and cloned was the first-known gene that makes skin cells able to sense warm temperatures. Subsequently, the investigator isolated a novel protein that mediates the body's ability to sense noxious cold temperatures through the skin.

In the years since it was founded, the Department of Cell Biology has more than doubled in size and has become a critical link between investigations of the chemistry and structure of biological molecules and the more complex behavior of cells and entire organisms.

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