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A new generation of optogenetic tools for research and medicine

Project team with participation of Humboldt University receives ERC Synergy Grant

The European Research Council (ERC) is providing 10 million euros in funding for an interdisciplinary, collaborative project to structurally and biophysically analyze selected photo-receptors and develop them into “OptoGPCRs”, light-controlled molecular switches with a wide range of applications in biology and medicine. The ERC Synergy Grant team consists of corresponding PI Gebhard Schertler head of the Division of Biology and Chemistry at Paul Scherrer Institute (PSI, Switzerland), and his colleagues Peter Hegemann (Humboldt University of Berlin, Germany), Sonja Kleinlogel (University of Bern, Switzerland) and Rob Lucas (University of Manchester, UK). Together they will demonstrate how OptoGPCRs can revolutionize our ability to control a wide variety of complex cellular processes with light.

“I congratulate the researchers and especially Mr. Hegemann very warmly on this great success. Synergy Grants are awarded for projects that substantially expand the frontiers of existing knowledge. This applies to Hegemann's research without a doubt. The development of light-controlled G-protein coupled receptors can revolutionize our understanding of the interaction of complex cellular processes,” says Prof. Peter A. Frensch, Vice President for Research at Humboldt University of Berlin.

The project funded by the ERC Synergy Grant “Switchable rhodOpsins in Life Sciences” - SOL is based on so-called bistable rhodopsins. Rhodopsins belong to the class of so-called G protein coupled receptors (GPCRs). There are hundreds of different GPCRs activating a variety of different G proteins and they play an important role in cell signaling in almost any cell type. Not surprisingly, they are the targets of a large variety of pharmaceuticals. Rhodopsins are light activated GPCRs, best known for their role as light receptors in the retina of the human eye. The vision receptors in our eyes lose their light-sensor, the vitamin A derivate retinal, upon activation and must be “re-assembled” in order to accept photons (light) again. Bistable rhodopsins however, keep their retinal and can in principle be activated and de-activated by multiple flashes of light without requiring any assembly, acting as true biological “switches”.

Using light to “switch” a cellular process on and off

"Our consortium pursues three main goals," says ETH professor Gebhard Schertler. "First, we want to elucidate the structure of the bistable rhodopsins in order to better understand how they function". Second, the researchers will use molecular biological methods to create bistable rhodopsins with novel properties which can be turned on and off by light of different wavelengths and effectively mimic the signaling effect of other GPCRs. "This will enable us to turn any G protein mediated signaling process in any cell type ON and OFF by light of a specific color", Schertler explains. “Our third goal is to use these switches to study the effect of G protein signaling in animals and to use this knowledge for the development of gene-therapeutics against human diseases.”

The second optogenetic revolution

The conception of the first generation of Optogenetics introduced a revolutionary concept in modern life sciences and provided an outstanding example how the basic research on molecular properties of proteins can translate into a practical application in cellular and animal systems. Optogenetics already had an enormous impact in neuro-sciences. However, it is so far limited to light-gated ion channels restricting its application essentially to stimulation of nerve cells. This has prevented a wide-spread application of this technology in the life sciences. So far, attempts to extend the range of optogenetic tools towards the photo-control of cellular receptors such as GPCR have failed. The combined synergistic and interdisciplinary expertise of Gebhard Schertler, an expert in structural characterization of these receptors, Peter Hegemann, a founding father of the first optogentic tools with an unmatched knowledge in biophysical characterization of photoreceptors, Rob Lucas, a world-leading expert on bi-stable rhodopsins in mammals and an expert in cellular assays, and Sonja Kleinlogel, a pioneer in gene-therapy using optogenetics, will provide the opportunity to deliver a toolbox of light controlled cellular receptors with wide-spread applications in biology and medicine.

This ERC Synergy Grant, funded by the European Union over a period of six years has therefore a realistic chance to become the catalyst for a “second optogenetic revolution” with PSI as leading house playing a pivotal role in moving the boundaries of modern life sciences.

Further information

ERC Synergy Grants 2020

Contact

Prof. Dr. Peter Hegemann
Institute for Biology
Humboldt University of Berlin

Tel: (+49) 030 2093 8830
hegemann@rz.hu-berlin.de

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