From molecules to tissues: Bridging the gap with three-dimensional electron microscopy

For many years, electron microscopy has been used to image cells and tissues at high resolution. This technology, invented in the early 20th century, provided breakthrough information in the virology and cell biology fields. Over the last 15 to 20 years, however, rapid advances in imaging and computation technologies have expanded the usefulness of electron microscopy into new realms. Electron microscopy is now poised to close a critical "gap" in the structural biology field.

The most commonly used methodologies in the structural biology field are X-ray crystallography and nuclear magnetic resonance spectroscopy (NMR). While each of these methods have yielded many key structures, many of the molecular complexes of greatest importance to biomedical research are either too large for NMR or are too conformationally heterogeneous for crystallization. Due to recent advances in a number of areas, electron microscopy now has the capability to determine structures of protein complexes like these to high resolution.

Our laboratory focuses on exploring the frontiers of electron microscopy, using this technology to determine three-dimensional structures of molecular complexes and whole cells at high resolution.

The long-term mission of the laboratory 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:

• Structural analysis of protein complexes involved in signaling and metabolism
• Enveloped virus glycoproteins: structures and applications to vaccine design
• 3D subcellular imaging with correlative light and electron microscopy
• Development of methods for high resolution cryo-EM