Engineering biology to use the power of light
We develop genetic tools for activation and detection of biological processes non-invasively with deeply penetrating near-infrared light. The technology is modular and can be customized for a variety of applications. Our tools will make drug discovery process faster and more efficient.
Target selection and validation in animals is a crucial step in drug discovery process. Less than 5% of selected drugs become successful in clinical trials. Therefore, target selection and preclinical studies require rigorous cell and animal models for human diseases and should allow screening of larger drug libraries and validation of larger number of compounds in vivo in shorter time.
Current technologies for activation of biological processes are based on chemical inducers, which may have off-target effects and are difficult to apply with fine precision in time and location. Available tools for activation of gene expression with light require visible blue-green light, which poorly penetrates tissues. To work in animal tissues, surgical implantation of light-delivery devices is required. Thus, technologies that allow to combine non-invasiveness of chemical inducers and precision and robustness of light-driven tools are required.
Current technologies for detection of biological processes in animals are based on bioluminescence imaging with luciferase reporters. These reporters require external chemicals, are too dim for cell microscopy and do not allow longitudinal imaging. Alternative bright GFP-based probes are not suitable for in vivo studies due to poor tissue penetration of visible light. Thus, there is a high demand for reporters that will allow multiscale imaging in both cells and animals and will be suitable for quantitative longitudinal studies, will be cost-effective, and will permit screening of larger drug libraries and validation of more targets in vivo.
Our technology allows non-invasive activation and detection of biological processes in both cells and animals using near-infrared (NIR) light, which penetrates one-inch deep inside living tissue. The technology is based on engineered genes derived from bacterial photoreceptors naturally sensing NIR light. These tools lack off-target effects and do not require exogenous chemicals.
The activation part is an optogenetic system called iBphP. iBphP consists of two proteins, phytochrome photoreceptor and its binding partner, whose interaction is induced by NIR light. By fusing iBphP components to cellular proteins, various protein-protein interactions can be controlled by light. Thus, we can activate gene expression/suppression, intracellular protein delivery, protein degradation, receptor/enzyme activation, metabolic pathways and cell fate. The only available alternative far-red light inducible system is inferior to iBphP because it is sensitive to dim daylight and requires external chemicals.
The detection part is based on NIR fluorescent proteins called iRFPs. iRFPs are used as easy as popular GFPs. First generation iRFPs are the brightest NIR fluorescent proteins and are in use by more than one hundred academic labs. Alternative probes require external chemicals or genes to function. Our second generation iRFPs are monomeric and can be fused to various cellular proteins to produce NIR reporters of important biological processes. These reporters permit quantitative longitudinal imaging in both cells and animals.
We develop customized NIR reporters in the forms of plasmids, engineered cells and animals. Customized activation and detection NIR tools based on our technology will allow easy screening of large libraries of drug candidates and straightforward rigorous validation of them in cells and animals. We design kits for popular applications of our technology in the form of ready-to-use plasmids, viruses, and cells. At present, iBphP optogenetic system, monomeric iRFPs and NIR biosensors are being evaluated by numerous academic labs and industrial laboratories.
Optogenetic system iBphP for activation of biological processes
Fluorescent iRFP reporters for detection of biological processes
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