Prof. Peter T C So

Summary: Many advances in biology and medicine are driven by the availability of new diagnostic tools. Our research focuses on the engineering of novel microscopy instrumentation and the application of these new tools to study biomedical problems. The problems tackled in my laboratory range from understanding the structure/function of single proteins, nature's smallest machines, to the development of a new non-invasive method to detect skin cancer. Research projects on the level of S.B., S.M., and Ph.D. are now available. No previous experience in biology is required. The available research topics in my laboratory can be categorized into molecular, cellular and tissue levels:

Molecular level projects:
(*) Single Molecule Study: Develop imaging technology with sufficient sensitivity such that even a single molecule can be detected. If a single antibody or a nucleic acid sequence can be characterized and located, one can envision greatly enhancing the capability of clinical diagnostic systems to detect and identify many infectious and genetic diseases. The dynamics and structures of these single protein molecules characterized by fluorescence spectroscopy will provide a new angle to study problems such as protein folding.
(*) Proteins as Nanomachines: Proteins are nature's smallest machines. Understanding protein functions will impact micromachine design. Proteins are in fact ready made nanomachines. Some function as motors and some function as gated valves. Incorporating proteins into traditional micomachines can greatly their range of functions.
(*) Nano-Manipulation: New methods to handle extremely small objects are emerging from our single molecular studies. A collaborative project with Prof. Mahadevan involves developing the technology required to control protein motion on biological membranes. This study will form the basis for fabricating protein patterned membranes which may function as novel biological sensors.

Cellular level projects:
(*) Single Particle Tracking: The 3-D transport process is critical in many areas of biology and medicine including membrane receptor internalization, phagtocytosis of antigenic material, bacterial invasion and virus-membrane docking. Two-photon microscopy can localize single particles in 3-D space with micrometer resolution. Using an imaging mechanism involving ultra-fast feedback control of the focal plane position, the trajectory of single particles under transport can be tracked in 3-D. One novel application, in collaboration with Prof. Lauffenburger, attempts to understand the relationship between osteoporosis around joint replacement implants and the release of harmful chemicals resulting from cellular uptake of wear debris.
(*) Intracellular Diffusion: Local viscosity in the cellular cytoplasm and the nucleus controls the kinetics of the cellular biochemistry. Two-photon correlation spectroscopy is a simple technique that deduces local viscosity by measuring the fluctuation of signaling molecules diffusing in and out of a small observation volume. We will attempt to generate diffusion maps of small molecules in cells.

Tissue level projects:
(*) Functional Deep Tissue Imaging: There is a lack of non-invasive diagnostic techniques for imaging thick tissue biochemistry and morphology at sub-cellular resolution. It is our hypothesis that a new optical biopsy technology capable of imaging tissue states to a depth of over 500 mm can be developed based on the deep penetration length of infrared light. This new technology will combine two-photon fluorescence and confocal reflected light microscopy. Two-photon micro-fluorometry performed in a microscope has been shown to be a viable method to assess thick tissue metabolic and biochemical states with femtoliter spatial resolution. Complementary cellular morphological information can be further obtained with confocal reflected light microscopy. The combination of tissue functional and morphological information has the potential to better diagnose cancer non-invasively.
(*) Two-Photon Endoscopy: If the feasibility of this two-photon deep tissue imaging technology can be proven in dermal models by successfully distinguishing healthy and malignant tissues, the design of an endoscopic attachment will be pursued to enable non-invasive cancer diagnosis in other organs such as the colon/rectum, the cervix, the prostate, the stomach and the throat.
(*) Non-invasive Wound Healing Studies: An understanding of re-epithelialization is important for the effective therapeutic treatment of both acute wounds and chronic non-healing wounds. During re-epithelialization, the epithelial sheet movement and the associated cellular migration, attachment and organization has been studied with traditional histological methods. With advances in molecular biology, the focus of these studies has shifted to the identification of molecular signals that control epithelial sheet movement and adhesion to the dermal matrix. Adhesion molecules, growth factors and cytokines all appear to play roles in wound healing. While the molecular approach is a powerful paradigm, the understanding of re-epithelialization processes is not complete without establishing a connection between these biochemical signals and the resultant morphological rearrangement of the healing epithelium. This goal has been out of reach as the opaque epidermis precludes effective microscopy imaging. In collaboration with Prof. Yannas, we will apply two-photon microscopy with deep tissue penetrating power to address this missing connection in our understanding between the cellular morphological states and the underlying biochemical driving forces in wound healing.