The Shaw Prize in Life Science and Medicine 2020 is awarded in equal shares to Gero Miesenböck, Waynflete Professor of Physiology and Director of the Centre for Neural Circuits and Behaviour, University of Oxford, UK, Peter Hegemann, Hertie Professor for Neuroscience and Head of the Department of Biophysics, Humboldt University of Berlin, Germany and Georg Nagel, Professor for Molecular Plant-Physiology, Physiological Institute – Department of Neuroscience, University of Würzburg, Germany for the development of optogenetics, a technology that has revolutionized neuroscience.

Understanding the brain is a daunting challenge. Each of the many billions of nerve cells in the human brain may make thousands of contacts with other neurons, resulting in an astronomical number of synaptic connections. The tools that allow us to trace and regulate neural networks in experimental animals have emerged in recent years and thanks to the discoveries of our Shaw Life Science Awardees for 2020: Gero Miesenböck of Oxford University, Peter Hegemann of Humboldt University, Berlin, and Georg Nagel of the University of Würzburg.

Neuroscientists had long sought methods to control the activity of individual nerve cells in order to observe the networks in which they communicate and define the processes that they control. Local direct activation of nerve cells by chemical or physical means has been used for over a century to detect and control voltage changes on cells in a network. The dream had been to control voltage changes indirectly by using light, allowing a less invasive and more precise means of controlling and observing the function of neural networks in an intact organism. The first key breakthrough came in 2002 with the development of an optogenetic tool devised by Miesenböck and colleagues. Using a naturally light-responsive protein, rhodopsin, which serves as the pigment on which we rely for vision, his team inserted the Drosophila (fruitfly) genes necessary to express the light-responsive rhodopsin into a vertebrate nerve cell culture. As a result, cells in the culture showed patterns of neuronal activity elicited by light. Building on this initial finding, Miesenböck was the first to show that this approach could be applied to the intact fruitfly and that by optically activating particular circuits one could alter the behaviour of the fly. In the first report Miesenböck concluded that “Since sensitivity to light is built into each target neuron, advance knowledge of its spatial coordinates is unnecessary. Large numbers of neurons can be addressed precisely and simultaneously without undesirable cross-talk to neighbouring neurons that are functionally distinct”. Miesenböck’s approach represented the first chapter in a new era of optogenetics.

In the application of this approach to animals, the fruitfly rhodopsin had certain technical disadvantages in terms of speed of response to light and genetic simplicity. Fortunately, and virtually simultaneous to Miesenböck’s work, a simpler photo-responsive channel protein emerged from studies on the detection of light by an algae, Chlamydomonas, that swims toward a source of light (phototaxis). Rhodopsins had been discovered and characterized in certain archaeal microorganisms, but the speedy phototactic response of the algal photoreceptor suggested that a single receptor protein may be sufficient to elicit a change in membrane current. In early work published in 1991, Peter Hegemann discovered a rhodopsin-based photocurrent in Chlamydomonas. After years of further work on this light response, Hegemann teamed up with Georg Nagel and in two papers published in 2002 and 2003, they demonstrated by gene cloning the existence of two light-responsive channel proteins, ChR1 and ChR2. Crucially, the team discovered that ChR2 elicits an extremely fast, light-induced change in membrane current when the gene is expressed in vertebrate cells. This discovery represented the second major step in the development of optogenetics.

The discovery of ChR2 by Hegemann and Nagel has enabled various functional applications in a variety of cells and tissues. In 2005, Karl Deisseroth with his graduate students Ed Boyden and Feng Zhang, and independently a few months later the team of Hegemann, Landmesser, and Herlitze documented the superior features of ChR2 as applied to nerve cells and vertebrate tissue. Since then, Deisseroth, Boyden, Zhang and others built many tools necessary to deliver both light and the genes precisely to neural networks deep in the brain.

As a result of these foundational, basic science discoveries, we now have the tools needed to visualize and precisely control specific neural networks in the brain of an animal. These discoveries presage a golden age of exploration of the mysteries of cognition and emotion with potential applications in psychiatric disorders that are only now being defined at the level of genes and cells.