Emerging methods in three-dimensional biological electron microscopy provide powerful tools and great promise to bridge a critical gap in imaging in the biomedical size spectrum. This gap comprises a size range of considerable interest in biology and medicine that includes cellular protein machines, giant protein and nucleic acid assemblies, small subcellular organelles and small bacteria. These objects are generally too large and/or too heterogeneous to be investigated by high resolution X-ray and NMR methods; yet the level of detail afforded by conventional light and electron microscopy is often not adequate to describe their structures at resolutions high enough to be useful in understanding the chemical basis of biological function.

The long-term mission of our research program is to obtain an integrated molecular understanding of cellular architecture by combining novel technologies for 3D biological imaging with advanced methods for image segmentation and computational analysis. Principal areas of current and future focus in the laboratory are:

• determination of the dynamic architecture of the bacterial chemotaxis apparatus and quantitative description of the mechanisms of signaling
  
  
• 3D structure, mechanisms of neutralization and cellular entry of HIV
  
  
• structure determination of dynamic molecular machines involved in energy transduction
  
  
• the development and application of novel technologies for three-dimensional electron microscopy, especially as applicable to cancer research

We are taking an interdisciplinary approach to achieve these goals by combining high-resolution electron microscopy with a variety of complementary biological and computational methods.