News and Publications

Cell Biology

Sandra Schmid, Ph.D., Chairman

ike cells themselves, cell biology stands between the whole organism and its molecular pieces, linking an organism's genetic content and its physiology.

The Department of Cell Biology was founded ten years ago, and has since doubled in size. The department's scientists work on a range of problems, including trying to understand the structure of a single molecule and how it functions, looking at the complex machinery of the cell, and studying the integration of populations of cells into tissues and organisms, whole animal physiology, and complex behavior.

Understanding the operations of living cells leads to discovery of new therapeutic approaches to such ailments as cancer, heart, lung, muscle, retinal, and neurodegenerative diseases. The department takes a multi-tiered approach toward understanding the basic mechanisms behind these problems, combining the sophisticated tools of molecular and structural biology, chemistry, and genetics with traditional cell biology.

One example of this is the recent work of Benjamin Cravatt, Ph.D., who characterized an important enzyme that mediates the sensing of pain. When you feel pain, your brain releases a compound called anandamide, which provides some natural pain relief by binding to receptors on cells on the rostral ventromedial medulla, a pain-modulating center of the brain.

However, this effect is weak and short-lived as other molecules, particularly an enzyme Cravatt identified called fatty acid amide hydrolase (FAAH), metabolize 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 that FAAH is the only enzyme responsible for doing so. The active site of FAAH is also unlike other similar enzymes, which may make it possible to block FAAH without repercussions elsewhere in the body.

Cravatt's hope is that controlling the action of FAAH could increase the longevity of anandamide and decrease pain.

Cravatt also directs the new Helen L. Dorris Institute for the Study of Neurological and Psychiatric Disorders of Children and Adolescents, which was recently established to uncover the pathological basis of neurological and psychiatric disorders and to enable the development of new therapeutic approaches. He will be leading the effort to recruit an interdisciplinary team of scientists to focus on understanding neuropathology in children and adolescents.

Other members of the Department of Cell Biology 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.

VISUALIZING LIVING CELLS

Klaus Hahn, Ph.D., has developed innovative fluorescent chemical dyes that can be attached to proteins to observe molecular signaling events that control cell migration in living cells -- events otherwise impossible to see. When a specific biochemical reaction happens in a protein, the dye switches on. By following changes in the overall fluorescence of the cells with a microscope and a digital video camera, Hahn can observe protein conformational changes, binding, or posttranslational modifications.

Similarly, Clare Waterman-Storer, Ph.D., who co-developed a technique called fluorescence speckle microscopy, is able to watch the dynamics of microfilaments and microtubules. These fibers, which together constitute the cytoskeleton, are assembled from small subunits, actin and tubulin, respectively, and are critical for controlling cell shape, cell movement, and cell division. In this technique, tiny amounts of fluorescent chemical dyes are attached to the actin or tubulin subunits, which are then injected back into the cell and become incorporated into the microfilaments and microtubules as they grow. One can then illuminate the cells under a microscope and train a video camera upon them to capture the dynamics of the cytoskeleton. 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 cellular structures. Recognizing and building on its world-renowned expertise in this area, TSRI is creating a center headed by Ron Milligan, Ph.D., that uses electron microscopy to create high-resolution structural images of large molecular complexes. Early next year, Milligan, together with his colleagues Drs. Francisco Asturias, Nigel Unwin, Mark Yeager, and Elizabeth Wilson-Kubalek, will move their groups into the newly constructed Center for Integrative Molecular BioScience (CIMBio). Here, TSRI will have the world's premiere center of high-resolution electron microscopy structural biology.

THE MOLECULAR MACHINES OF THE CELL

CIMBio seeks to combine the use of x-ray crystallography and electron microscopy to unravel the structures and mechanisms of action of the large molecular assemblies of the cell. These assemblies, rather than individual proteins, are the molecular machines of the cell -- 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. The protein components of these machines may be studied by x-ray crystallography, and maps of the machines can be calculated from electron images. Combined with the x-ray structures of the components, this technique can yield a detailed description of the structure and action of the entire machine.

Two new recruits to the department, Associate Professors Bridget Carragher and Clint Potter, who are former co-directors of the Imaging Technology Group of the Beckman Institute for Advanced Science and Technology at The University of Illinois at Urbana -- Champaign, are creating algorithms for automated data collection and analysis, which should simplify the technique of electron microscopy and allow throughput to be increased dramatically. As mathematical modelers, they are also developing algorithms to figure out the machinery of the cell. Cell structures interact with one another in a dynamic way, and the modeling tools of advanced mathematics are becoming more useful as more of the complexity of cells is understood.

Completion of the human genome has provided a list of the cell's interacting parts. The efforts of researchers in the Department of Cell Biology are focused on understanding how all of these parts work together to form a whole.

John Yates, Ph.D., a pioneer in the field of proteomics, is developing methodologies to look at protein expression changes in whole cells. Often the regulation of protein activity is controlled through post-translational modification and the interaction of one protein with another. Members of the Yates laboratory have developed sophisticated tools and computer programs to detect these subtle protein differences, and they hope that by comparing normal cells with cancer cells, they will identify potential weaknesses that can be targeted by drug therapy.

Sandra Schmid, Ph.D., has discovered a new enzyme belonging to the serine/threonine kinase family. Schmid has provided evidence that the enzyme regulates two types of cellular machines -- the actin cytoskeleton and membrane trafficking -- helping to spatially and temporally control cellular events.

In its first decade, the Department of Cell Biology has become a critical link between chemistry, structure, and cellular function. As scientists begin to study more complex cellular and organismal behavior, using ever more sophisticated methods, cell biologists will open new doors to the prevention, diagnosis, and treatment of human disease.