Scientific Report 2008

Center for Integrative Molecular Biosciences

The Center for Integrative Molecular Biosciences (CIMBio) was created in 2002 to foster collaborative research dedicated to elucidating structure-function relationships of the cell's molecular machines. During the past year, our faculty made a number of noteworthy scientific advances. The following list highlights some of this groundbreaking science.

Gaudenz Danuser continued his cutting-edge work on computational and microscopic methods for quantifying cellular processes, in particular those involving the dynamics of the cellular cytoskeleton and endocytosis. He published several high-profile papers in Nature Methods and Developmental Cell. He was honored for this work by the Biophysical Society, which awarded him the Michael and Kate Bárány Award for Young Investigators for his "outstanding seminal contributions in diverse areas of cell biology, particularly to our understanding of cell cytoskeleton dynamics and function using speckle microscopy.”

Mark Yeager and colleagues published a detailed molecular model of the full-length capsid protein of HIV type 1 in Cell. This protein forms a cone-shaped capsid shell around the genome of the virus. The structure reveals novel features of interactions between subunits in the HIV type 1 capsid that may serve as new targets for antiviral therapy.

Several groups in CIMBio study the assembly and functional characterization of virus particles, including Marianne Manchester, Anette Schneemann, John E. Johnson, and M.G. Finn. Drs. Manchester, Schneemann, and Yeager collaborated to develop a novel virus-based nanoparticle that displays parts of the anthrax toxin cellular receptor on its surface. This engineered particle prevented cell death by anthrax toxin and, when complexed with the anthrax protective antigen, served as a novel vaccine antigen that could protect animals from toxin challenge after a single immunization. Published in PLoS Pathogens, this work received wide media coverage from Science Daily, The Scientist, and the Associated Press.

Dr. Manchester also collaborated with Dr. Finn to develop novel virus-based nanoparticles that specifically target tumor cells, with the long-term goal of targeting drugs to tumors in the body. Their work, published in Chemistry and Biology, showed that particles could be specifically targeted to folic acid receptors that are upregulated on the surface of tumor cells. Using novel chemical methods to vary ligand density, the scientists tailored the particles for receptor recognition. They also developed novel virus-based contrast agents for magnetic resonance imaging.

Dr. Finn and his group continued their studies on displaying carbohydrates on the surface of virus-based nanoparticles and constructing polyvalent glycan ligands on the surface of particles. In collaboration with James Paulson, they showed the usefulness of the particles as carbohydrate vaccines. This work was highlighted in the Journal of the American Chemical Society.

Claudio Joaziero was the recipient of an American Cancer Society Research Scholar award. He published a study in PLoS ONE on the genome-wide characterization of E3 ubiquitin ligases. Until this work, hundreds of human E3 ligase-encoding genes were known to exist, but their approximate number and complete inventory were unavailable, despite their critical importance for many biological processes and diseases. Dr. Joaziero and his group discovered a previously uncharacterized human E3, termed MULAN, that localizes to mitochondria, regulates the organelle's morphology and distribution, and activates NF-κB signaling. The discovery of MULAN opens the way to determining how mitochondrial signaling and dynamics are linked, which could lead to new ways of thinking about these processes. PLoS ONE selected this article, from among more than 120 others, to be highlighted as the top research they have published on cell signaling. Dr. Joaziero also served as the co-organizer of the American Association for Cancer Research meeting, Ubiquitin and Cancer: From Molecular Targets and Mechanisms to the Clinic, held in San Diego.

Several CIMBio postdoctoral fellows and doctoral candidates received prestigious fellowship awards this year. Kristopher Koudelka was awarded fellowships from the Achievement Rewards for College Scientists Foundation, Inc., and the Fletcher Jones Foundation. Nicole F. Steinmetz was awarded a fellowship from the American Heart Association. Jessica Petrillo was awarded a Ruth L. Kirchstein Postdoctoral Fellowship from the National Institutes of Health and a Science and Technology Policy Fellowship from the American Association for the Advancement of Science.

Between November 10 and 16, 2007, the National Resource for Automated Molecular Microscopy (headed by Bridget Carragher and Clint Potter) held the third in a planned series of biennial training courses designed to provide extensive exposure to electron cryomicroscopy and image analysis. This year, a major goal of the course was to discuss some of the challenges in electron cryomicroscopy that remain to be solved, including improvements in specimen preparation, imaging, processing, and reconstruction required to reach higher resolutions and solve small structures with limited symmetry or conformational variability. The course had 111 official participants, which included many leaders in the field.

Finally, a 5-day training workshop was held at the National Resource for Automated Molecular Microscopy on March 10 to 14, 2008. The purpose of the workshop was to introduce the Leginon automated imaging system to those groups who want to use it at their home institutions. Participants were from the following institutions: University of Pittsburgh School of Medicine, Howard Hughes Medical Institute/Janelia Farm Research Campus, New York University Medical Center, Biocenter Finland, Max Planck Institute of Molecular Cell Biology and Genetics Dresden, Weizmann Institute of Science, Yale University, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.