Researchers to develop new optogenetic tools for biology and medicine

Reviewed by Emily Henderson, B.Sc.November 8, 2020

The European Research Council (ERC) is providing € 10 million in funding for an interdisciplinary and collaborative project in the structural and biophysical analysis of selected photoreceptors and their development into “OptoGPCR”, light-controlled molecular switches with a wide range of applications in biology and medicine.

The ERC Synergy Grant team is comprised of the corresponding principal investigator Gebhard Schertler, head of the Division of Biology and Chemistry at PSI, 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 OptoGPCR can revolutionize our ability to control a wide variety of complex cellular processes with light.

The ERC Synergy Grant funded project “Switchable rhodOpsins in Life Sciences” – SOL – is based on the so-called bistable rhodopsins. Rhodopsins belong to the class of so-called G protein-coupled receptors (GPCRs).

There are hundreds of different GPCRs that activate a variety of different G proteins and play an important role in cell signaling in nearly all cell types. Not surprisingly, they are the targets of a wide variety of pharmaceutical products.

Rhodopsins are light activated GPCRs, best known for their role as light receptors in the retina of the human eye. Upon activation, the visual receptors in our eyes lose their light sensor, the retinal vitamin A derivative, and must be “reassembled” to accept photons (light) again.

Bistable rhodopsins, on the other hand, maintain their retina and can in principle be activated and deactivated by multiple flashes of light without requiring any assembly, acting as real biological “switches”.

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

“Our consortium pursues three main objectives,” says Gebhard Schertler. “First, we want to clarify the structure of bistable rhodopsins to better understand how they work.”

Second, the researchers will use molecular biological methods to create bistable rhodopsins with novel properties that can be turned on and off by light of different wavelengths and effectively mimic the signaling effect of other GPCRs.

This will allow us to activate and deactivate any G-protein-mediated signaling process in any cell type in light of a specific color. 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 therapies against human diseases. “

Gebhard Schertler, Principal Researcher Correspondent and Head of the Division of Biology and Chemistry, Paul Scherrer Institut (PSI)

The second revolution of optogenetics

The first generation conception of optogenetics introduced a revolutionary idea into modern life sciences and provided an outstanding example of how basic research on the molecular properties of proteins can translate into practical application in cellular and animal systems.

Optogenetics has already had a huge impact in neuroscience. Until now, however, it has been limited to light-gate ion channels, limiting its application essentially to the stimulation of nerve cells. This prevented the widespread application of this technology in the life sciences.

So far, attempts to extend the range of optogenetic tools towards photo-control of cell receptors such as GPCR have failed.

The combined synergistic and interdisciplinary experience of Gebhard Schertler, an expert in the structural characterization of these receptors, Peter Hegemann, one of the founding fathers of the first optogenetics tools with unmatched knowledge in the biophysical characterization of photoreceptors, Rob Lucas, a world leading expert on bistable rhodopsins in mammals and expert in cell assays, and Sonja Kleinlogel, a pioneer in gene therapy using optogenetics, will provide the opportunity to provide a toolbox of light-controlled cell receptors with widespread applications in biology and medicine.

Schertler and Lucas were part of an international project funded by the Human Frontier Science Program, which provided important preliminary data for this ERC SynergyGrant, which is funded by the European Union for a period of six years.

This ERC grant has a realistic chance of becoming the catalyst for a “second optogenetic revolution” with PSI as the leading institution playing a vital role in extending the boundaries of modern life sciences.