A bottom-up approach to the rational design of new bioluminescence emitters

This research will improve our molecular level understanding of bioluminescence for the rational design of new near-infrared emitters for advanced bioluminescence imaging applications.

Bioluminescence is the emission of light by living organisms. It is one of Nature's most spectacular phenomena and continues to challenge those who try to understand it. The yellow-green glow of fireflies is one of the brightest and most beautiful examples of bioluminescence. The biochemical process involves the catalytic oxidation of a small molecule (luciferin) by an enzyme (luciferase) to form an electronically excited oxyluciferin that subsequently relaxes to its ground state by emitting light.

Harnessing bioluminescence for imaging applications has revolutionised the biosciences. Bioluminescence imaging is now a standard tool for visualising molecular and cellular processes in vivo. However, more advanced applications are limited by reduced sensitivity in deep tissue arising from the absorption of visible light by blood and tissue. New far-red and near-infrared bioluminescence systems for enhanced sensitivity and resolution in deep tissue have recently become available; however, they are limited by their brightness and narrow spectral range. There is a pressing need for bright, multicolor, far-red and near-infrared emitters.

To date, modifications to bioluminescent systems have relied on incremental changes and small library-based approaches. We propose to use a fundamentally new, bottom-up approach. We will use state-of-the-art spectroscopy measurements and quantum chemistry calculations to learn which electronic states and molecular motions of far-red and near-infrared luciferins are important in the competing non-radiative relaxation pathways that reduce the brightness of bioluminescence and we will learn how luciferase enzymes tune the bioluminescence wavelength. We will then use this information to design new, bright bioluminescent emitters for multicolour, far-red and near-infrared bioluminescence imaging.

This project and its results will transform our molecular level understanding of the relationship between chemical structure and bioluminescence, which will provide us with the capability to develop the tools required for new imaging and biotechnology applications to explore new aspects of biology and medicine. It will also advance our general understanding of the role of complex environments on the electronic structure and relaxation dynamics of photoactive molecules, which will provide important information for the rational design of a wide range of new photoactive materials by scientists around the world in industry and academia. Photoactive molecules are involved in a range of emerging technologies, such as solar energy and information technology, and the results from our increased understanding will thus have potential widespread impact. The best of the far-red and near-infrared bioluminescent systems characterised will be developed into new noninvasive diagnostic tools for the health and well-being of society. Ultimately, these will be commercialised and lead to new jobs and wealth creation.

The research personnel working on the project will develop into multidisciplinary scientists capable of solving future emerging problems through the use and development of chemistry. They will not only learn state-of-the-art techniques in spectroscopy, computer simulation and molecular synthesis, but they will learn how to work in an interdisciplinary project that requires good communication between the different parts to ensure the success of the project. The new knowledge and techniques developed in the project will have impact across chemistry, as outlined in the beneficiaries section, helping to keep the research base of the UK at the forefront of international research.

To bring the work to the wider public, the link between the timeless beauty of the firefly and the non-invasive lighting up of biological function will be presented at public events. This provides an obvious focus to explain the delicate balance of how molecules and light interact, and how this can be used to benefit society.