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Illuminating biological processes with chemistry

Photo: Stephen Miller

Our laboratory has two main objectives: 1) non-invasive optical imaging of the intracellular environment with fluorescence and bioluminescence, and 2) spatial and temporal control over protein function. To achieve these goals, we synthesize small molecules that absorb and/or emit light.

  • Optical probes of the intracellular environment

Fluorescent molecules. Study of the intracellular environment using fluorescence is limited by the inherent absorbance of living tissues. Most optical probes in use today absorb and emit light in the visible wavelength region. Absorption of visible wavelength light by cellular components (e.g., flavins, porphyrins) generates excited state molecules that can give rise to background fluorescence and phototoxicity. In whole animals such as the mouse, absorption of light by the hemoglobin in blood is so great that visible wavelength fluorescence is not viable for imaging.

Living tissue is most transparent to light beyond the visible range, in a spectral region known as the near-IR (650-900 nm). Although this is the ideal spectral window for any optical probe of living cells or organisms, most near-IR fluorophores are unsuitable for use in the intracellular environment because they either lack cell-permeability or give high-background labeling of cellular organelles and membranes. One of our major goals is the design and application of new near-IR fluorophores and probes that can freely enter living cells and facilitate studies of specific intracellular events.

Bioluminescent molecules. Luciferase-catalyzed light emission can also be used to report on the intracellular environment, and can be used in live animals such as the mouse. Nonetheless, the properties of luciferase are inherently limited by the ability of the luciferin substrate to access the luciferase, and by its photophysical properties (e.g., emission wavelength). Work in our lab is directed toward the development and optimization of luciferases and luciferins for applications ranging from high-throughput screening to bioluminescence imaging in mice.

  • Photocontrol of protein function

To exert spatial and temporal control over cellular processes, our lab is using the power of chemistry to synthesize molecules that can block the activation and interactions of specific proteins. Upon irradiation with light, these molecules either fall apart or rearrange to restore protein function. For example, the location and timing of GTPase activation is critical for proper cell function, but is still poorly understood. We will use this photoactivation approach to study these rapid processes in living cells using fluorescence microscopy.

Post Docs

Postdoctoral positions are available in the Miller laboratory to investigate and extend the scope of bioluminescence imaging.

Lab projects range from molecular-level studies of the mechanism of luciferases, to non-invasive imaging of specific biological processes and disease states in live animals. 

Motivated and inherently curious critical thinkers with backgrounds in biology, chemistry, or both are encouraged to apply.

Rotation Projects

Rotation Projects

Work in our lab uses optical imaging to study live cells and organisms. This multi-disciplinary approach brings together the areas of synthetic organic chemistry, molecular biology, biochemistry and cell biology, with translation into mouse models of disease.

1) Broadening the scope of bioluminescence: Bioluminescence results from the chemical generation of light that occurs when a luciferase enzyme oxidizes its small molecule luciferin substrate. We have synthesized a wide variety of novel luciferin substrates designed to improve the ability to detect bioluminescence signals. In parallel, we have mutated luciferases to best accommodate these substrates, and have also found that a homologous protein in the fruit fly can act as a luciferase. Projects in the lab range from basic molecular-level biochemical, chemical, and evolutionary studies of luciferases and luciferins, to powerful applications such as imaging of enzyme activity and drug action in the brains of live mice.

2) Fluorescent probes beyond the visible range: Fluorescent sensors of enzymatic activity, metal ions, and small molecules allow the optical detection of biologically-important molecules. However, most of these sensors are based on visible-wavelength fluorophores that suffer from photoxicity and high background. These probes thus have limited utility in live cells, and are generally unusable in live organisms such as mice. We are designing and constructing sensors that fluoresce in the near-IR, beyond the visible range, which is most suitable for non-invasive optical imaging of the physiological state of live cells and organisms.


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  • imaging
  • probe