Chemistry is the study of understanding natural phenomena from the viewpoint of atoms and molecules, and creating new materials. The most fascinating aspect of chemistry is to create materials that no one has ever touched before, and their use for the benefit of the world. For example, natural polyether compounds with molecular weights of several thousand can now be synthesized artificially, and some of the synthetic methods have led to the development of pharmaceutical compounds. On the other hand, life has created even larger proteins (with molecular weights of 10,000 or more) and achieved higher functions that cannot be duplicated artificially. How such functions were created from atoms during evolution remains a mystery. However, it is possible to artificially modify proteins and create “next-generation proteins” by adding new functions to the natural proteins.
Among various functional proteins, we focus on photoreceptor proteins that absorb and emit light, and aim to evolve these proteins to acquire particular function and apply them to analytical techniques in life science research. One theme is the development of molecular imaging technology using Green Fluorescent Protein (GFP), its mutant forms, and bioluminescent proteins (Luciferase) (see Live “Watching”). The technology to visualize the functions of live biomolecules by spatiotemporally tracking their changes has been a driving force to dramatically deepen our understanding of life, and continues to develop further. It is truly amazing and inspiring to be able to observe the behavior of molecules of interest in living cells and individual animals and plants through a lens.
Such molecular imaging has a history of more than 30 years, and some of the applications have been greatly extended to practical use. We are also applying our proprietary biomolecular imaging technology to research for compounds (Live “Screening”). Universities and research institutes have a library of compounds that are potential drug candidates. We aim to select functional molecules from this library by using our originally developed imaging technology and probe molecules, and to utilize them for basic research and development of new drugs.
Furthermore, “Optogenetics,” a technology that uses light to manipulate the activity of specific molecules in living organisms, has emerged and is making a significant contribution to the rapid development of life science research. These optical manipulation tools are based on photoreceptor proteins from plants, algae, and other organisms. Based on these photoreceptor proteins, we are developing technologies to manipulate various intracellular signals in space and time (Live “Control”). We aim to realize quantitative manipulation by collecting data on intracellular signals after manipulating specific molecules with light and building mathematical models.
We also have interests in the development of new analytical techniques useful for forensic analysis based on data on the IR and Raman spectral data, and the development of system-integrated microscopes through collaborative research. We aim to discover new principles in analytical chemistry and develop new detection methods to unravel the mysteries of life using our originally-evolved proteins and methodologies.
‘Seeing’ while living
We are developing new methods and technologies to visualize how, when, and where intracellular small molecules and proteins express their functions. So far, we have developed methods of fluorescence imaging of endogenous RNAs, protein-protein interactions, intracellular protein phosphorylation, and intracellular dynamics of proteins of interests in living animals. We are now developing luminescent probes, consisting of molecular recognition tools connected with a luminescent protein using protein engineering techniques
‘Screening’ while living
The identification of new compounds that control physiological functions relies heavily on the development of screening methods. The establishment of new screening methods is expected to lead to the identification and discovery of novel molecular species. We have developed a novel approaches to high-throughput screening of functional peptides from gene libraries and to comprehensive analysis of proteins transported into mitochondria and intracellular vesicles. In addition, we have developed a unique cell line expressing luminescent probes to screen for compounds that regulate cell fusion and GPCR activity, which was practically applied for chemical library screening.
‘Controlling’ while living
If the quantity and function of a protein to be studied in vivo can be controlled by external light irradiation, it will be possible to obtain temporal and spatial information related to the protein. Using photoreceptor proteins, we are developing a new concept for spatiotemporal manipulation of various intracellular signals. Furthermore, we aim to realize quantitative light manipulation by constructing a mathematical model of the intracellular signals. By combining the optogenetics with imaging techniques, we aim to develop innovative analytical methods for non-invasive manipulation and observation of molecules of interests deep inside the body.