Researching the Foundations of Life
An innovative microscope for gentle 3D imaging of living cells
Much of what is known about how life developed, how its biological processes work together, how diseases are caused and how they can be treated is due to state-of-the-art high-resolution fluorescence microscopy. Yet this ingenious method also has a major disadvantage: it has an effect on and even damages the organisms studied – a factor that dramatically limits its possible applications. How can this dilemma be resolved?
Dr. Thomas Kalkbrenner, Dr. Jörg Siebenmorgen and Ralf Wolleschensky developed a solution: the innovative microscope system ZEISS Lattice Lightsheet 7. The system opens entirely new perspectives for research in biology, medicine, and pharmacology by linking lattice light sheet microscopy with various innovative optical technologies. This protects sensitive living samples from being damaged by the laser light used during microscopic examination. At the same time, the team found a way to make the complex technology easy to use.
The People Behind
Dr. Thomas Kalkbrenner
Dr. rer. nat. Thomas Kalkbrenner was born in 1971 in Überlingen, Germany. He studied Physics at the University of Konstanz. He has been working in Advanced Development at ZEISS Microscopy since 2008 and became Team Leader and Lead Architect in the Special 3D product line in 2020.
Dr. Jörg Siebenmorgen
Dr. rer. nat. Jörg Siebenmorgen was born in 1979 in Pasewalk, Germany. He studied Physics at the University of Hamburg. He has been working in Advanced Development at ZEISS Microscopy since 2011.
Dipl.-Phys. Ralf Wolleschensky was born in 1972 in Jena, Germany. He studied Physics at the Friedrich Schiller University Jena. He has been working at ZEISS since 1998 and became the Head of Advanced Development at ZEISS Microscopy in 2009.
Reining in the Laser
The problem for researchers studying living cells with fluorescence microscopes is the illumination: the intensities of the laser radiation used are higher than those of the sun by a factor of 1000 or more. This intense illumination can permanently damage living cells.
A significant reduction of this photo damage is achieved with light sheet microscopy: unlike all other microscopes, the laser beam – in the form of a light sheet – is applied only in the area within the focus of the objective lens. While this works well for larger organisms, the laws of optics still prevent the transfer of this technology to cell biology. "We had to rein in the laser in a special way so that light only goes where a researcher wants to look and without unduly damaging cells," explains Kalkbrenner. "So we built on the idea of lattice light sheets from Nobel Prize winner Eric Betzig and took it further."
Looking Through the Glass at an Angle
On top of this, the team had to completely rearrange the objective lenses because the cells grow on the cover slips in culture vessels like Petri dishes or multiwell plates. One would have to look from below at an angle through the cover glass – an impossible task for a microscope objective, because the distortions that occur prevent any imaging.
So they developed a completely new type of microscope optic based on adaptive freeform elements that allows to look through the sample vessels ‒ at an angle and from below ‒ at the cells inside without artefacts.
Using Standard Sample Carriers
The team managed to compensate the smallest deviations in carrier dimensions and sample position. Especially the multiwell plate formats, which are so important for the development of active agents in the high content screening process, are accessible to a light sheet microscope for the first time.
All this has been developed to create an easy-to-use, compact system with high automation potential.
Exploring the Living Cell
ZEISS Lattice Lightsheet 7 enables, for the first time, biomedical researchers to observe living cells live and in 3D for hours or even days. They study how, for example, the cells react to certain active agents, or what happens when viruses or bacteria enter cells.
A research group from Melbourne, Australia uses the system to study the malaria parasite, which is responsible for almost half a million deaths annually according to the World Health Organization (WHO). With ZEISS Lattice Lightsheet 7, they were able to capture this parasite, which is only one µm in size, as it invaded a living blood cell. For the first time, it was possible to study different stages of this highly complex parasite's life cycle live and in 3D.
In cancer research, too, scientists have already gained new insights with ZEISS Lattice Lightsheet 7. Prof. Markus Sauer from Julius Maximilian University in Würzburg studies immunotherapies, which potentially offer better chances of survival. Immune cells are removed from patients and reengineered so that they can better identify the tumor cells. These more effective CAR-T cells are then infused back into the person being treated.
An exact understanding of the interaction between these CAR-T cells and tumor cells is decisive for optimizing personalized immune therapy in terms of impact and minimal side-effects. Here, lattice light sheet microscopy, with its ability to capture individual molecules, plays an especially important role.
The Deutscher Zukunftspreis
The Deutscher Zukunftspreis – the German President's Award for Innovation in Science and Technology – has been presented annually since 1997 and is one of the highest accolades for scientific achievement in Germany. It honors exceptional achievements in technology, engineering and the life sciences as well as software and algorithms that have resulted in viable products. Every year, the prestigious jury handpicks three research teams from a vast array of projects in a multi-stage selection process, and each team's innovation is shortlisted for the award in the final round of the competition. Alongside their innovative achievements, the jury also evaluates the development's economic and social potential. This year's award was presented in Berlin by German President Frank-Walter Steinmeier on 26 October 2022.
Read the press release.
Further information on the nominations and the German Future Prize.