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Professor Marco Fritzsche has joined the Kennedy Institute as the Principal Investigator of the Biophysical Immunology Laboratory (BPI), as part of a joint appointment with the Rosalind Franklin Institute. His lab is leading the development of a lattice light sheet microscope that will significantly advance the study of live cells.

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Marco Fritzsche has a vision. His mission is to untangle the biological significance of mechanobiology on the human immune response in health and disease. In lay terms, what this means is understanding the biological processes taking place at the across scales from single cells via tissues to whole organs level in response to a mechanical signal or change. As an example, how do immune cell sense and respond to inflammation during tissue wound healing? What is allowing the cells to full-fill their function during this immune response integrating information about the mechanical properties of its surroundings and begin to activate a repair function?

By understanding these underlying processes the BPI Laboratory at the Kennedy Institute aims to make significant advances in the understanding of the human immune response leading to improvements in diagnostics and treatments of patients.

But much of this depends on observing cells over time in vivo (live in the cells or tissues), something that is often not possible with conventional tools and microscopy techniques. So, one of the key goals of the lab is to develop the required technology with the right sensitivity to observe the biology unfolding in its micro-environment in space and time. One of these tools is a combination of advanced volumetric and super-resolution microscopy.

"It was in 2014, while I was studying for my post doc, that Eric Betzig came to talk in Oxford about the new lattice light sheet microscope. I was fascinated by the technology, and I approached him and asked if I could visit his lab," said Marco. "And this started the relationship."

The lattice light sheet microscope was developed by physicist and Nobel Laureate Eric Betzig at the Janelia Farm Research Campus, USA. The microscope overcame one of the greatest challenges in imaging live cells which was to observe them without light affecting their behaviour. Using thin sheets of light to illuminate the cell by, tissue, or organism one slice at a time, the overall exposure to harsh laser light is reduced resulting in a gentler effect on live samples and producing very low phototoxicity/photobleaching effects.

The technology in the lattice light-sheet enables researchers to capture previously unseen dynamic biological phenomena in three dimensions, in multiple colours, and for multiple hours per experiment.

Around a similar time, a good friend of Marco's, Dong Li, developed the TIRF-SIM. This super-resolution microscope offers the best compromise between sub-diffraction spatial and temporal resolution, which makes it for the ideal instrument to study the activation of immune cells.

In December 2016, Marco initiated a collaboration with Eric and Dong to bring their technology to Oxford and with the support of Michael Dustin, Professor of Immunology at the Kennedy Institute, built the TIRF-SIM super-resolution microscope, the second microscope in the world of its kind.

Professor Dustin said: "The TIRF-SIM offers a unique combination of gentleness, speed and sensitivity at interfaces used to model critical biological processes in health and disease. Marco was instrumental in bringing this technology to Oxford and we are delighted to now welcome him to the KIR Faculty. Working across both the Kennedy Institute and the Rosalind Franklin Institute he will take a leading role not only in the development of new imaging systems, but also to ensure these technologies are applied to pressing biological questions in areas of interest at the Institute.

The new lattice light sheet microscope being developed by the Biophysical Immunology Laboratory will be five years in the making and will be one of few of its kind in the world. It will combine the advantages of the minimally invasive lattice light sheet microscope with the high resolution SIM technology, which are both at the forefront of providing the technology to researchers to study cells at the single cell level.

"The idea is that you cannot do many of these measurements in live animals, but you can mimic them," explained Marco. "We can design a biomimetic chip which basically mimics the architecture of an organ, for example a tumour microenvironment. We can mechanically and biologically design it within a microchip, then study the cells under different environments. Because of the minimally invasive lattice light sheet, we can study the cells for up to 2-3 weeks, gaining an understanding of their history, studying individual interactions of the cell within the biologically designed environment, and we can change the microenvironment to analyse the cells' response."

Marco's team is small, something he learned from Janelia Farm. His group's approach is to take the new technologies and develop them specifically for the biological question, rather than develop a technology and try to apply it to a need. "This obviously has a huge demand on the people working with us, because we are expecting within the group that everybody basically becomes an expert on the imaging, becomes an expert in the immunology, and becomes an expert in programming and data analysis. So, they need to be at an extremely high level at all these disciplines," said Marco.

Marco's role is jointly funded by the Rosalind Franklin Institute and the Kennedy Trust for Rheumatology Research. He leads the BPI between the Kennedy and the Rosalind Franklin Institute, which is focused on biophysics and aims to transform life science through new technology. "At the Kennedy we provide a biological angle and are focused on the immunology, so there will be a synergetic effect moving forward together."

Professor Angus Kirkland, Correlated imaging theme lead at the Rosalind Franklin Institute said: "Each imaging technique provides key data, but adding them together produces a bigger picture that is more than the sum of its parts."