Optogenetics: a light switch for brain cells

Your brain holds around 90 billion nerve cells, wired together like a giant tangle of fairy lights. For a long time scientists could only watch the tangle flicker. They could not reach in, flip one small group of bulbs, and see what happened.

The answer came from a tiny green alga that swims toward light. On its surface sits a protein that works like a door with a light sensor built in. When blue light hits it, the door swings open and charged particles rush into the cell. In a nerve cell, that rush is how a signal starts.

That is optogenetics: teach a chosen nerve cell to listen to light, then use light to ask it what it does.

Nerve cells talk in electrical pulses. A pulse begins when ion channels, protein pores in the cell membrane, open and let positive ions flow in. That inflow makes the inside of the cell less negative. If the change is big enough, the cell fires an action potential, a brief spike that passes the message on.

In the early 1990s Peter Hegemann, at the Max Planck Institute for Biochemistry in Martinsried, recorded how the green alga Chlamydomonas reacts to light. An electrical impulse appeared about half a millisecond after a flash. In the human eye, light triggers a chain of chemical steps before a channel opens, which takes at least 10 milliseconds. Hegemann proposed that the alga skips the chain: one protein both catches light and forms the channel. Many doubted him: no known ion channel responded to light alone.

Karl Deisseroth, then starting a lab at Stanford, asked Nagel for the gene. His team put it into rat nerve cells grown in a dish. Blue light made the cells fire. The result came out in 2005. In 2007 the team delivered the gene to one type of nerve cell in the motor cortex of living mice, shone light through a thin optical fibre, and made the whiskers move.

The power comes from genetics. Researchers deliver the gene, often with a modified virus, so that only one chosen type of nerve cell makes the channel. Only that type then responds to light. Scientists could now switch a defined cell type on and test whether it causes a behaviour. Before, they could mostly show that the two happen together.

In 1999 Francis Crick argued that understanding the brain would need a way to switch one neuron type on or off in an alert animal while leaving its neighbours alone, and he named light as the ideal signal. Earlier tools each missed a requirement. Miesenböck's chARGe (2002) needed three Drosophila genes and a G-protein cascade, so spike timing was loose. P2X2 receptors with caged ATP, and photoswitchable tethered ligands on engineered potassium channels, needed a chemical delivered from outside. What was missing was one genetically encoded protein that turns a photon directly into membrane current within milliseconds.

Two properties made ChR2 the right actuator. First, it is a channel, not a pump. Archaeal pumps such as halorhodopsin move one ion per absorbed photon; a channel lets many ions run down their gradient, fast enough to match action potentials. Second, Nagel noticed that the trace retinal already in mammalian cells is enough, so no chromophore has to be added. Boyden, Zhang, Bamberg, Nagel and Deisseroth used this in 2005 to drive spike trains in cultured hippocampal neurons with millisecond precision. In 2007 Aravanis and colleagues in the Deisseroth lab coupled laser diodes to optical fibres, expressed ChR2 in layer 5 excitatory neurons of the vibrissal motor cortex, and evoked whisker movements in vivo.

Clinical use is early and experimental. In 2006 Zhuo-Hua Pan's group restored light responses in degenerated mouse retinas with AAV-delivered ChR2 in retinal ganglion cells. In 2021 Sahel, Roska and colleagues injected an AAV encoding the red-shifted channel ChrimsonR into a blind patient with retinitis pigmentosa; with goggles projecting light pulses onto the retina, the patient could distinguish high-contrast objects on a table, and EEG showed object-related visual cortex activity. That was one case.