Scientists who worked out how to control brain cells with light have won this year’s Nobel prize in physiology or medicine. Karl Deisseroth, Peter Hegemann and Georg Nagel were honoured for their research into “light-gated ion channels and optogenetics”.
Peter Hegemann, at Humboldt University of Berlin, and Georg Nagel, at the University of Würzburg, wanted to understand how a tiny, single-celled alga called Chlamydomonas senses light. Light-sensing is not unique to animals with eyes: organisms throughout the living world use light to detect their surroundings and respond to changes in their environment. Even single-cell organisms have proteins that respond to light. These proteins are used to move towards or away from light, to generate energy and to respond to the various demands of a 24-hour day.
Hegemann and Nagel discovered that Chlamydomonas has a beautifully ingenious mechanism of light detection that relies on a single protein called channelrhodopsin.
Channelrhodopsin is built into the outer membrane of the algal cell. Part of the protein faces the water outside the cell and part faces the inside. The protein also contains a small molecule called retinaldehyde, which is able to absorb light.
When light hits the retinaldehyde inside channelrhodopsin, it changes shape. This makes the channelrhodopsin protein change shape too. That change opens a tiny passage through the cell membrane. Positively charged particles, including sodium, can then flow from the water outside the alga into the cell. This movement of charged particles sends a signal inside the alga that helps it swim.
How fantastic to have solved such an interesting biological question, but why the Nobel prize in physiology or medicine? The answer lies in the way nerve cells work. Nerve cells use the movement of charged particles (called “ions”) across their membranes to control their activity. When positively charged particles flow into a nerve cell, they can make it more active.
The researchers realised that if they could put channelrhodopsin into nerve cells, they might be able to switch those cells on simply by shining a light on them. That is exactly what Hegemann, Nagel and the third Nobel-prize winner, Karl Deisseroth, a psychiatrist and bioengineer at Stanford University in California, went on to do.
Ill. Niklas Elmehed © Nobel Prize Outreach, CC BY
Switching on nerve cells with light
The ability to control nerve cells with light is called optogenetics. It has become a powerful research tool because scientists can use it to switch specific groups of nerve cells on and off and see what happens.
First, scientists deliver the gene for channelrhodopsin to the nerve cells they want to study. The gene is usually carried into the cells by a virus that has been altered so that it cannot cause disease. The cells then make the channelrhodopsin protein, which makes them respond to light.
In animals such as mice, scientists can shine light into the brain through a thin optical fibre. When the light reaches the cells, channelrhodopsin opens and the cells become active. Nearby nerve cells that do not contain the protein are unaffected.
Light can be aimed at a very small part of the brain and switched on and off extremely quickly. This makes optogenetics a powerful way to investigate how the brain works. For example, if scientists want to know whether a particular group of nerve cells is involved in memory, sleep, sensation or movement, say, they can switch those cells on with light and see what happens.
In one experiment in 2012, a team at the Massachusetts Institute of Technology gave mice a mild electric shock in a particular cage. They used optogenetics to tag the nerve cells in the brain’s memory centre that were active during that the fear-conditioning experiment. Days later, in a different cage, they switched those cells on with light. The mice froze in fear, as if they remembered the shock.
Mice that were not shocked did not freeze, which showed that the light was reactivating a specific memory. Deisseroth was one of the study’s authors.
Optogenetics has transformed scientists’ ability to investigate how the brain and nervous system work. It may also have a future as a treatment. Optogenetics is already in early-stage clinical trials for people with retinal degeneration. In these trials, researchers introduce light-sensitive proteins into nerve cells that remain in the retina after the cells that normally detect light – called rods and cones – have been lost. This can make surviving cells respond to light and restore some vision.
Researchers are also investigating whether optogenetics could eventually be used to treat neurological conditions, including Parkinson’s and epilepsy.
This year’s Nobel prize celebrates work that started with a question that may sound esoteric: how do Chlamydomonas swim toward light? This question has no obvious practical importance. It doesn’t address an urgent need in human health, nor is it a clear route to riches. The success of optogenetics is an illustration of the importance of continuing to ask questions simply to understand the world around us because it’s impossible to predict where knowledge will take us.
Robert Lucas receives funding from the European Research Council, the Wellcome Trust, the UKRI (via the Medical Research Council and the Biotechnology and Biological Sciences Research Council) and Fight for Sight. He is a named inventor on patents awarded for the use of rod opsin in vision restoration.