NIGMS supports research that will lead to a better understanding of cell structure, function and regulation at the most basic level. A growing number of imaging strategies and techniques enable fundamental breakthroughs at cellular and subcellular levels. NIGMS funds projects applying and developing a wide range of imaging applications and technology, including optical/fluorescence microscopy for cellular imaging, electron microscopy, single molecule spectroscopy, live cell imaging and the development of probes and sensors.
Since the inception of the microscope, researchers have been looking inside cells to decipher structural and functional details. In the early years, observations were limited to the identification of large organelles. During the last 3 decades, critical advances have revolutionized the field of cellular imaging. A significant milestone in the mid-1990s was the introduction of genetically encoded fluorescent probes, such as green fluorescent protein (GFP), that enabled investigators to study processes in living cells in real time. In recent years, it has become clear that cellular imaging—at all levels of resolution and for both live and fixed specimens—is providing new cellular information in an unprecedented way.
Over the past 10 years, NIGMS has been a leader in organizing and promoting important imaging initiatives for the scientific community. These include one of the first NIH Common Fund (formerly the NIH Roadmap for Medical Research) programs, Exploratory Centers for the Development of High Resolution Probes for Cellular Imaging, which brought together nine multi-investigator teams to develop new technologies for creating higher sensitivity probes for biological imaging in living cells. NIGMS also led the re-issuing of this initiative. NIGMS developed a separate initiative to support the evaluation of promising but unproven technologies for the detection of single molecules and single molecular events inside cells: the Molecular Probes for Microscopy of Cells program. Related initiatives include program announcements for the Single Molecule Detection and Manipulation and Nanoscience and Nanotechnology in Biology and Medicine.
The bulk of NIGMS-funded research in cellular imaging, however, is investigator-initiated R01 research. Most of these projects utilize some form of imaging for studying a specific biological problem.
NIGMS also hosts a number of meetings and workshops.
The Institute supports about 1,200 research and training grants that focus directly on improving strategies for cellular imaging or that employ cellular imaging as one of the tools to investigate a biological problem. In Fiscal Year 2012, these grants totaled approximately $400 million. While all NIGMS divisions and centers fund work in this area, the majority is supported by the Division of Cell Biology and Biophysics. A list of program directors who manage cellular imaging grants and their contact information is available at https://www.nigms.nih.gov/Research/specificareas/cellimaging/pages/contactus.aspx.
Of the more than 70 Nobel Prize-winning scientists whose work has been supported by NIGMS, five have been recognized for important breakthroughs in cellular imaging. They include Osamu Shimomura, Martin Chalfie and Roger Y. Tsien for the discovery and development of GFP (2008); and Christian de Duve and George E. Palade for discoveries related to the structural and functional organization of the cell (1974).
Cellular imaging has and will continue to have a significant impact on biological research and our understanding of interactions between molecular components within the cell as well as the dynamics of single molecules in normal and abnormal cells. For instance:
- Imaging strategies have enabled investigators to use and develop an array of fluorescence techniques to make observations and measurements across many different biological systems with a detection limit currently approaching 20 nanometers.
- Fluorescence microscopy has seen a renaissance during the last 15 years and is now recognized as a useful complement to other more static techniques because of its minimal perturbation to the cell, its versatility, its use across many length scales and its usefulness for real-time observations.
- The discovery and development of genetically encoded fluorescent probes, such as Green Fluorescent Protein (GFP), has spurred an interest in identifying new dyes, optically-active materials, labeling strategies, smaller fluorescent proteins and nanoparticles for characterizing cellular structures and processes that allow proteins to continue functioning normally.
- Single molecule studies, designed to yield information about molecular motion, behavior and fluctuations over time and space, have increased. Compared to in vitro studies, real-time observations of single molecules in live cells lets researchers observe the behavior of and differences between individual molecules, rather than the averaged behavior of an ensemble of molecules. Although still a challenge, imaging of single molecules in living cells provides fundamental knowledge about cellular structure and function at the molecular level.
- Defining the internal organization of cells using electron microscopy and other techniques has laid the foundation for understanding key cellular pathways and processes. These studies, coupled with other types of imaging as well as atomic resolution structural studies, have provided a wealth of information about cellular structure and function. A continuing goal is to use an array of strategies in imaging, structural biology, genetics, proteomics and biochemistry to gain more insight into the functioning of the cell. Cellular imaging is a key component in the overall strategy and perhaps the most useful for achieving real-time information about cellular dynamics.