A new microscope system will capture how cells in embryos, organs, and tumours communicate across distances, using light pulses to measure molecular interactions in real time. Current microscopes cannot simultaneously image large groups of living cells at high speed and molecular resolution. This gap prevents researchers from watching how cells collectively organise into complex three-dimensional structures, or how they respond to mechanical and chemical signals during migration. The MEGA-FLIM system solves this by combining ultrafast light detection across a million-pixel field with two-photon excitation for 3D reconstruction, and adds optogenetic control to actively steer cell behaviour with light. If successful, the system will directly impact drug discovery and synthetic biology. It will allow researchers to build organ-on-chip or tumour-on-chip platforms that mimic real tissue environments, making preclinical testing more reliable. The commercial market for advanced imaging and light-controlled cell systems stands to gain a tool that does not currently exist. While the research is fundamentally about understanding collective cell behaviour, that understanding is the prerequisite for reliably engineering tissues or diagnosing how cell signalling fails in disease.
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Embryos, organs and tumours are composed of many cells, which interact with each other and communicate across distances of several cells. While it is routine to study single cells under a microscope, it is much more difficult to study collectives due to their size, light scattering properties and complexity. Fluorescence lifetime imaging (FLIM) and FRET (Forster resonance energy transfer) use the principles of energy transfer that occur when a light particle (photon) jumps from an excited fluorescent donor molecule to a nearby acceptor, thus changing the fluorescence lifetime of the donor. FLIM is used to measure close molecular interactions inside of living cells by measuring this lifetime change. We will combine physics, engineering, computation and biology to build a new light microscopic system, with extremely high spatial and temporal resolution. We call our system MEGA-FLIM and we will use it to study larger cell collectives of cells to discover how cells communicate and organise in response to both mechanical and chemical signals. MEGA-FLIM will allow much faster collection of light signals across a much larger field than previously possible. We will also develop technology to use light to control cell behaviour across these collectives using the technique called optogenetics. Our unique team of optical physicists, bioengineers and biologists is ideally placed to break down current barriers, leading to landmark discovery in each of these fields. Why do we need a new FLIM microscope system? Commercial systems are lacking that allow, simultaneously: - fast acquisition (0.1 second or faster) so as to allow real-time measurements in live cells or embryos - across a widefield area with high resolution (1 million pixels or higher), so as to allow imaging of the full cell environment and large collectives - with high time resolution (50-100 pico seconds), so as to allow precise discrimination of lifetimes - two-photon excitation, so as to allow precise full 3D reconstruction of cell collectives. - widefield optogenetic activation (light-controlled cell behaviour), so as to allow study of the dynamics of collectives in the presence of complex activation stimuli that act across multiple sites. What problems will this new system solve and what impact will it have? -MEGA FLIM will provide a system that will allow us to interrogate living systems at molecular resolution and discover how cells collectively signal using both chemical and mechanical signals to steer when they migrate. This kind of steering allows cells to recognise each other and other cell types and to form complex patterns in 3 dimensions (like in an organ or an embryo). -Our new system will be of great commercial interest, as it will advance capabilities in imaging and optogenetic control of cell behaviour with light. -By building a system whereby we can discover new pathways governing how cells behave in collectives, we will gain the ability to reliably and predictably control collective cell behaviour. This discipline, known as synthetic biology, is highly desirable for medical and commercial use in building organ/tumour-on-chip systems or creating physiologically relevant systems to use in drug discovery.
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