News and Publications

Chairman's Overview

Sandra Schmid, Ph.D.

The discipline of cell biology is rapidly evolving in exciting new directions. Our department is keeping pace with these changes and, in many instances, is leading the way. This evolutionary growth spurt is fueled by many factors, including (1) the complete sequencing of the human genome and the availability of a list of parts that must be assembled to drive complex cellular and organismal behaviors, (2) the development of new tools that facilitate the biochemical and structural characterization of large protein complexes that function as cellular machines, (3) the development of sophisticated live-cell imaging technologies to visualize single-molecule dynamics in living cells, (4) the revolution in combinatorial chemistry that enables us to design and identify chemical inhibitors as powerful tools, (5) the recent application of mathematics and computer programming to analysis of complex images, and (6) as our knowledge base expands, the ability to apply mathematic models to help probe mechanisms and predict complex cell behaviors.

The new Center for Integrative Biosciences expanded in January of this year with the opening of phase 2. As founding members of a program for the study of live-cell molecular dynamics, Klaus Hahn, Velia Fowler, Kevin Sullivan, and Clare Waterman-Storer now have laboratories in newly designed, state-of-the-art facilities. Using microscopy, biochemistry, molecular biology, and chemistry, these groups, together and individually, are defining cytoskeletal dynamics involved in the control of cell shape, motility and polarity, organelle movements, chromosome segregation, and cytokinesis. For example, by manipulating levels of tropomodulin 3, a tropomodulin isoform expressed in microvascular endothelial cells, Dr. Fowler and her group established that the isoform acts as a negative regulator of cell migration by controlling actin assembly dynamics at the leading edge of migrating cells. In addition, Dr. Waterman-Storer and colleagues used the fluorescent speckle microscopy technique they developed to show direct links between actin dynamics and microtubule dynamics at the leading edge of migrating cells, establishing that the coordinated activity of both of these cytoskeletal elements drives cell migration.

The research of the live-cell program will be greatly enhanced by the arrival of Gaudenz Danuser, who has transferred his laboratory for computational cell biology from the ETH in Zürich, Switzerland, to TSRI. Dr. Danuser is an engineer and computer scientist with a strong interest in cell biology. He and his group wrote a sophisticated package for the quantitative analysis of fluorescent speckle microscopy data that allows them to track the hundreds of thousands of fluorescing markers that spontaneously appear and disappear and that provide insight into the live-cell kinetics of cytoskeletal assembly and disassembly reactions. Computational analyses of the kinetics provide the framework for the development of biophysical and mathematical models that suggest underlying molecular mechanisms and make testable predictions to drive further experimentation.

Although phase 1 of the Center for Integrative Biosciences is only 1 year old, we accomplished a major objective, establishing the National Resource for Automated Molecular Microscopy. Headed by Bridget Carragher and Clint Potter, the long-term goal of the resource is to develop a completely automated system for molecule microscopy, from sample preparation to data acquisition to calculating final 3-dimensional structure. The large molecular assemblies that are the target of study for the laboratories of Ron Milligan, Francisco Asturias, and Mark Yeager are extremely challenging and often impossible objects for study by x-ray crystallography but are ideal candidates for structural analysis by electron microscopy. However, using electron microscopy to determine structure is time-consuming, tedious, and meticulous work. Automation will bring this technique into the mainstream and increasingly provide insight into the moving parts of dynamic molecular machines. In the meantime, the tedious and meticulous method works, and according to a published commentary on his studies, Dr. Asturias continues to apply these techniques with "virtuosity" in unraveling the structure of the multisubunit RNA polymerase II and its equally complex regulatory cofactors. His research provided new insight into the mechanism of RNA transcription that could not be ascertained from the static image of this protein machine as revealed by x-ray crystallography.

Most diseases that cause catastrophic loss of vision do so as a result of abnormal growth of blood vessels. Martin Friedlander and his colleagues made exceptional progress this year in defining mechanisms of neovascularization of the retina. Particularly important is the discovery that bone marrow­derived endothelial precursor cells, that is, adult stem cells, can be injected into eyes and are correctly targeted and incorporated into the neovasculature. In collaboration with Paul Schimmel's group, Department of Molecular Biology, they found that transfection of these cells can be used to deliver a new antiangiogenic inhibitor to reduce devastating neovascularization. On the flip side, these stem cells, which are strongly neurotrophic, can be used to regenerate the vasculature in mice with inherited retinal degeneration. Thus, this discovery should have a marked impact on the treatment of eye disease.

In other important translational research, Mark Yeager, in a collaboration supported by the Skaggs Scholars in Clinical Science, developed a pig model for restenosis, a common postoperative complication associated with the insertion of coronary stents. Using this model system and human oligonucleotide arrays, Dr. Yeager and his colleagues hope to identify new targets for prevention of restenosis.

Active recruitment efforts attracted several outstanding new faculty members, in addition to Dr. Danuser, to our department. Uli Mueller and Lisa Stowers join us at the Institute for Childhood and Neglected Diseases. Dr. Mueller and his colleagues use elegant mouse genetic approaches to study the role of integrins in brain development and the mechanisms of mechanosensory perception in the inner ear. Dr. Stowers, who is generously supported through the Helen L. Dorris Child and Adolescent Neurological and Psychiatric Disorder Institute, is defining the repertoires of chemosensory neurons responsible for the innate olfactory response, again using forward and reverse mouse genetics. A. (Natasha) Kralli and her group moved from the Biozentrum in Basel, Switzerland, to continue their work at TSRI on cofactors that regulate steroid hormone signaling in response to stress. Peter Kuhn moved from Stanford University, Stanford, California, to coordinate efforts with the Palo Alto Research Center in developing new technologies for high-throughput functional proteomics.

Current faculty members continue to excel and win national recognition. Mark Ginsberg was named a Fellow of the American Association for the Advancement of Science. Dave Loskutoff received a Distinguished Career Award from the International Society of Thrombosis and Haemostasis. Ardem Patapoutian was named a Damon Runyon Faculty Scholar. Sandy Shattil was named Editor-in-Chief of Blood. Clare Waterman-Storer was a finalist for the W.M. Keck Foundation Distinguished Young Scholar in Medical Research Award and was named the Keith Porter Fellow. Ben Cravatt received the prestigious Eli Lilly Award in Biological Chemistry. As usual, our faculty serve on numerous editorial boards, serve on scientific advisory and review boards, and act as organizers for important meetings and symposia, fulfilling leadership roles in the broader scientific community.

It seems that we are evolving in the right directions, and the future of cell biology looks bright indeed.