We propose to develop the scanning tunneling microscope (STM) for molecular-level imaging of the ultrastructure of biological samples in their natural hydrated stated. The STM affords a real-space view of the surfaces of materials at atomic dimensions, while avoiding many of the difficulties and expense associated with electron microscopy. In particular, the STM does not need a high-vacuum environment, being able to function in aqueous solution. Furthermore, staining or shadowing pretreatments that may lead to ambiguities in relating microscopic images to real structures are unnecessary. The potential of the STM for biological purposes is exciting, but almost totally untapped. The STM has the capability not only to reveal biological structures in aqueous solution; it may even be possible to observe biochemical processes occurring in real-time at the molecular level, and perform atomic-scale micromanipulation of biomolecules. However, a number of problems exist that prevent the present use of the STM for providing interpretable high-quality images of biological materials in a natural state- as yet the STM has only produced a very few poor quality images of dried biological samples. These difficulties are both of a practical nature connected with working in solution, and in scientific understanding of image formation. We plan experiments to improve our understanding of the process of image generation in water solutions. We will also investigate the effect of interactions of the instrument with the sample. In addition we intend to develop methods of anchoring samples to a substrate for microscopic examination such that the sample retains its integrity. Although it is not clear at this time how successfully these difficulties can be overcome, this work could provide the foundation for a new technology that will provide new understanding of biological structures and biochemical processes at the molecular level, and have profound implications in many areas of biomedical research.
