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
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
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.