A new type of genetically encoded optical marker, called a bioharmonophore, could let scientists image living tissues deeper and more clearly than current fluorescent dyes allow. The problem is that today’s fluorescent probes have hard limits. They fade under prolonged light (photobleach), saturate under intense illumination, and cannot distinguish many cell types at once because their signals overlap. These shortcomings make it difficult to watch cellular behaviour deep inside organs or track multiple cell populations simultaneously in real time. Bioharmonophores sidestep these issues by emitting a signal called second harmonic generation, which does not photobleach or saturate. Their signal profiles are extremely narrow and tunable to any wavelength, so researchers could label many different cell types in the same tissue volume without confusion. Because the markers are genetically encoded, any lab can obtain them through standard repositories. This is fundamental tool-building science. If it works, it will give biologists a sharper window into tissue physiology, injury response, and disease progression. The immediate impact is on research capability, not daily life—but better imaging tools have historically accelerated discoveries in regeneration, cancer, and ageing that eventually reach the clinic.
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Observing life down to a cellular resolution provides the best means for understanding the mechanisms underpinning tissue physiology, maintenance, injury response and ageing. Intravital light microscopy has revolutionised our ability to witness cellular behaviours in their native context and thus track dynamics in real time. The development of various genetically encoded fluorescent proteins has introduced powerful and versatile imaging tools. The ease of expressing fluorescently tagged proteins or obtaining fluorescently marked cell populations through straightforward genetic methods has yielded a wealth of information about the function and behaviour of many biological processes in development and disease. Nevertheless, there remain many areas in which significant improvement is urgently needed. Biologists are keen to image more deeply into living tissues and organs, yet imaging depth is limited by both the scattering and absorption of visible light in tissue. Conventional fluorescent probes also suffer from photobleaching, which refers to the irreversible destruction of the dye when excited for extended periods or with excessive intensity. Additionally, signal saturation creates an intrinsic limitation on fluorophore brightness even under intense illumination – limiting imaging sensitivity particularly in deeper tissue where signal detection is already challenging. Furthermore, the number of cell types that can be observed simultaneously within the same tissue volume remains limited, as the broad and often overlapping signal profiles of fluorescent dyes greatly reduce specificity. To overcome these challenges, we propose the development of transformative genetically encoded bioharmonophores as superior optical markers for precision imaging. Bioharmonophores emit a distinct signal known as second harmonic generation (SHG). This signal, which can be generated and detected using two-photon microscopy — a widely established technique in biomedical research — circumvents key limitations of existing fluorescent probes. SHG signals are not subject to photobleaching or saturation. Additionally, bioharmonophores have unparalleled narrow signal profiles that can be finely tuned to any desired wavelength, enabling tailored observation of specific cell types in deep tissues. Being genetically encoded, these labels will be immediately accessible to a broad scientific audience through repositories such as Addgene. This innovative project aims to transform live-tissue imaging by providing new tools for studying tissue physiology, cellular behaviour and disease mechanisms with unprecedented depth, clarity and specificity.
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