August 31, 2012
Sometimes it is the unprepossessing organisms that take science a giant step forward. The single-cell freshwater alga Chlamydomonas reinhardtii and the salt lake archaebacterium Natronomonas pharaonis are prime examples of this. They have light-sensing proteins for orientation and energy production known as rhodopsins. Scientists have used these proteins for several years to activate or deactivate nerve and muscle cells with high temporal and spatial accuracy with the aid of light, but without using electrodes.
Peter Hegemann began to study the light perception of algae back in 1985 when he was working at the Max Planck Institute of Biochemistry in Martinsried. From 1995 onwards, Georg Nagel and Ernst Bamberg at the Max Planck Institute of Biophysics succeeded in transferring different bacterial rhodopsins to frogspawn and human kidney cells, as well as in describing their electrophysiological properties. Between 2002 and 2003 Peter Hegemann, who was now at the University of Regensburg, Georg Nagel and Ernst Bamberg were able to demonstrate a remarkable property of algal rhodopsins: by transferring the rhodopsin gene to egg cells of the clawed frog they found that the algal rhodopsins unify the light receptor and ion channel in a single protein. When blue light is incident, the protein channel becomes permeable for protons and positive potassium and sodium ions. The cell potential is therefore shifted towards the positive. The algal rhodopsins, called channel rhodopsins by the researchers, therefore differ from many other light-sensitive proteins such as rhodopsins in the human eye, which do not have their own directly light-activated ion channel.
Taking these results as their basis, various groups of researchers throughout the world now began to use the channelrhodopsins as tools to investigate cells. Researchers including the three pioneers thus activated channelrhodopsins in the nerve cells of the nematode Caenorhabditis elegans (together with Alexander Gottschalk, University of Frankfurt) and in hen embryos and mice (together with Stefan Herlitze, University of Bochum). With channelrhodopsin-2 and halorhodopsin it proved possible to control the mobility of the nematode, for example, as halorhodopsin “pumps” negatively charged chloride ions into the nerve cell after activation with yellow light. It thus shifts the cell potential further towards the negative and inhibits the cell. This allowed the nerve cells of the worm to be activated with blue light and deactivated with yellow light.
Karl Deisseroth of Stanford University also recognised at an early stage the enormous potential of the channelrhodopsins for the neurosciences, as the activity of nerve cells is based on the influx of sodium ions - i.e. precisely those ions which also flow through channelrhodopsin. In 2005, together with Georg Nagel and Ernst Bamberg, he transferred channelrhodopsin-2 into nerve cells of the brains of rats, and was thus able to use optogenetics to trigger action potentials for the first time. Moreover, he also succeeded in activating channelrhodopsins in the brains of free-moving rats. He did this by conducting the light through glass-fibre cables directly into the brain. This enabled him to undertake investigations in a variety of animal species as to how nerve cells generate behavioural patterns such as movement, fear or social behaviour and how learning and memory processes occur.
Optogenetic technology has also been useful in investigating neurological diseases such as epilepsy, Parkinson’s disease, depression and age-related blindness. Genetically modified animals that display disease symptoms similar to human symptoms and which have been provided with channelrhodopsin or halorhodopsin genes are important scientific tools. The objective is to use light to activate or deactivate nerve cells in the brain or in the eye of the animals in a controlled way. The intention is to remove the relevant disease phenomena or allow mice that are blind due to a genetic defect to regain their sight. The successful animal experiments open up possibilities for biomedical applications. For example, in September 2011, a major pharmaceutical company signed a licence agreement for the patent of Bamberg, Hegemann and Nagel for the exploitation of the channelrhodopsins for the gene therapy of age-related blindness.
The four researchers honoured by the Gertrud Reemtsma Foundation are also working to further improve the channelrhodopsins for optogenetics. This requires biophysical and biochemical investigations for the more detailed understanding of the molecular mechanism of the channels. The scientists have already described variants that manage with less light, react more rapidly and are sensitive to different light wavelengths.
The K. J. Zülch Prize 2012 will be awarded on 7 September 2012 from 10:00 a.m. to 12:00 noon in the Hansasaal of the Historic Town Hall in Cologne. The laudatory speech for Ernst Bamberg, Peter Hegemann and Georg Nagel will be delivered by Benjamin Kaupp from the caesar research center. Jens Brüning from the Max Planck Institute for Neurological Research will deliver the laudatory speech for Karl Deisseroth. After the speeches, Georg Nagel and Karl Deisseroth will report on the development of optogenetics and future applications.