News and Publications

Chairman's Overview

Sandra Schmid, Ph.D.

This year marks the 10th anniversary of the Department of Cell Biology. In its first decade, the department grew from the original 20 members to its current faculty of 32. This growth enhanced its strength in the areas of cellular biochemistry and structure and led to diversification into areas such as sophisticated imaging of cellular dynamics, chemistry, proteomics, and genetics.

The recent completion of the human genome sequence provided the list of parts that make up the human body. Now the multidisciplinary tools of cell biologists are required to place these parts in their functional context within the cell and build the "blueprint" of human physiology. The cell biologists at TSRI are uniquely poised to take advantage of the wealth of genomic information in their efforts to obtain the mechanistic understanding of complex biological processes required to develop new therapies and diagnostics.

During the past year, members of the department made numerous important discoveries, a few of which are highlighted here. Other discoveries are described in the reports of the individual investigators.

Illustrative of the advantages of combining chemical approaches with biochemistry, physiology, and genetics, Ben Cravatt's group discovered that fatty acid amides function as endogenous agonists of cannaboid receptors and that these signaling molecules are major determinants in controlling pain sensitivity. These researchers discovered an enzyme, fatty acid amide hydrolase, that catabolizes these signaling molecules. Members of the group generated mice that lack this enzyme and found that the resulting accumulation of fatty acid amides greatly lowers the animals' sensitivity to pain. In collaboration with Dale Boger's group, Department of Chemistry, Dr. Cravatt's group discovered small-molecule inhibitors of fatty acid amide hydrolase that may lead to powerful new treatments for pain control.

Cystic fibrosis is a devastating disease caused by the inability of a mutant ion transporter protein, CFTR, to adopt the correct conformation needed to be recognized by the cell's secretory apparatus for transport to the cell surface, where the activity of CFTR is needed to maintain clear passages in the lung. As a result, an otherwise fully functional CFTR remains trapped inside the cell. Bill Balch's group, working on the mechanisms of processing and secretion of newly synthesized membrane proteins, discovered that CFTR normally follows an unusual itinerary to the cell surface. The discovery of this new pathway could lead to identification of new targets for enhancing the delivery of mutant CFTRs to the cell surface.

A cell's genetic information is contained within the nucleus, yet the gene products must be synthesized in the cytosol. Transport between these 2 compartments occurs through gated nuclear pores, whose structure has been elucidated by Ron Milligan. How do mRNAs traverse the nuclear membrane, and how do the proteins involved in transcription and RNA processing enter the nucleus? Larry Gerace and members of his laboratory provided new insight into both mechanisms. They found that a gradient of binding affinities of transported molecules with nuclear pore constituents guides cargo molecules from one side of the pore through to the other side. These researchers also identified viral proteins that facilitate either the import of viral DNA into the nucleus or the export of viral RNA. Interference with these mechanisms may lead to new antiviral therapies.

A critical, but often overlooked, aspect of protein function is the tight regulation of where and when in the cell proteins are active. Klaus Hahn and Clare Waterman-Storer and their staff members developed biochemical and chemical methods and complementary new imaging technologies to monitor protein activity in live cells in real time. Dr. Hahn's group, in collaboration with Gary Bokoch, Department of Immunology, and Martin Schwartz, Department of Vascular Biology, visualized the activation of a signaling GTPase that controls cell migration, for example, during wound repair or metastasis. Dr. Waterman-Storer and her colleagues used these high-tech, high-power movies to reveal the dynamic interplay between actin and microtubule assembly that drives cell migration.

Although access to the complete DNA sequence of the human genome is now available, much remains to be done to identify all of the gene products, or proteins, encoded in these sequences. The next phase is proteomics, the identification of the proteins in complex mixtures and placement of these proteins in specific functional contexts. John Yates is a world-renown expert in this area; he developed many of the methods needed for increased sensitivity and resolution. He and the members of his laboratory led an effort to identify the complete proteome of the yeast, which consists of more than 5000 proteins, as a starting point for applying these technologies to the more complex human genome.

Faculty members of the Department of Cell Biology continue to be recognized by the national and international scientific communities for outstanding research efforts and successes. Phil Dawson was the recipient of the Alfred P. Sloan Award; Francisco Asturias received an award from the Leukemia and Lymphoma Society; Steve Kay was awarded the Genetic Prize from the Japanese Society for the Promotion of Science; Clare Waterman-Storer was given an Achievement Award in Optical Microscopy; and Ardem Patapoutian received a Basil O'Connor Starter Scholar Research Award from the March of Dimes. Velia Fowler and Mark Yeager were promoted to full professor, reflecting their outstanding reputations in and significant contributions to the scientific community both within and outside TSRI.

One exciting new area of expansion begun in the past year was the contribution of cell biologists to the newly constructed Institute for Childhood and Neglected Diseases, which is described elsewhere. New departmental members Mark Mayford, Colin Fletcher, and Ardem Patapoutian are joined by Shelley Halpain and Steve Kay in an effort to use forward and reverse mouse genetics and cell biological approaches to unravel the complexities of sensory and motor neuronal development, learning, and memory. Elizabeth Winzler is developing methods to analyze whole genomes of pathogens, such as the organism that causes malaria, to identify potential new therapeutic targets.

A second initiative is the establishment of a new Center for Integrative Molecular Biosciences. The initial phase of this project, guided by Ron Milligan, seeks to take advantage of and to enhance the department's world-class expertise in electron microscopy in structural biology. High-resolution x-ray crystallographic and nuclear magnetic resonance methods are being used by other researchers at TSRI to probe the 3-dimensional structure of individual proteins and protein domains. Often these proteins work in the cell in the context of large multiprotein machines, whose conformational changes drive cell motility, transcription, translation, membrane trafficking, and so forth. Structures of these complexes and their conformational changes are most readily accessible by using electron cryo-microscopy and image reconstruction techniques, which were pioneered by Nigel Unwin. The Center for Integrative Molecular Biosciences will help synergize the efforts of our already impressive group of structural microscopists, including Mark Yeager, Francisco Asturias, Alok Mitra, and Elizabeth Wilson. We are excited to have recruited 2 additional faculty members, Bridget Carragher and Clint Potter, formerly codirectors of the imaging technology group at the University of Illinois, to augment our efforts in this area. Together these researchers will continue to provide structural and functional insight into the mechanisms of molecular motors, transcriptional regulation machinery, viral assembly and structure, membrane channels and pumps, protein chaperones, and other important macromolecular complexes.