Medicine Nobel rewards controlling neurons with light - critical summary review

Light as a switch for nerve cells

There is a method in neuroscience called optogenetics, a word that combines "opto", from the Greek for visible, and "genetics". In practice it means controlling biological processes with light, and it works in two steps. First, researchers make a chosen group of cells produce a protein that responds to light. Then they illuminate those cells. Depending on the protein, the light either fires the cell or silences it, and it does so with great precision in time: the scientist controls exactly when the stimulation happens and how long it lasts.

Applied to the brain, this turns a selected group of neurons into something close to a switch. Researchers have used it to study circuits involved in movement, sleep, pain, hunger, reward, attention and social behaviour, and in conditions such as Parkinson's disease and epilepsy.

That is the backdrop against which this week's news arrives.

The prize announced in Stockholm

On Monday, October 5, the Nobel Assembly at the Karolinska Institute, Sweden's medical university, awarded this year's Nobel Prize in Physiology or Medicine to Karl Deisseroth, of Stanford University and the Howard Hughes Medical Institute in the United States, Peter Hegemann, of Humboldt University of Berlin, and Georg Nagel, of the University of Würzburg, in Germany. The citation reads "for their discoveries concerning light-gated ion channels and optogenetics". They share 12 million Swedish kronor, around 1.2 million dollars.

The wording matters. The committee is not pointing at a therapy, it is pointing at an instrument. "Optogenetics offers opportunities to map the brain in a way we could previously only dream of," said Per Svenningsson, chair of the Nobel Committee for Physiology or Medicine. Thomas Perlmann, secretary-general of the Nobel Assembly, said the method "makes it possible to switch the activity of individual nerve cells on or off in a living brain" and that it is used today in laboratories around the world. Folha de S.Paulo, a Brazilian daily, noted that the committee itself acknowledged the trio's work remains essentially basic research.

From an alga that swims toward light to a mouse's whiskers

The chain begins far from the human brain. In the 1960s, research on the green alga Chlamydomonas showed that these single-celled organisms move toward light. In the early 1990s, Hegemann, then at the Max Planck Institute of Biochemistry in Germany, wanted to understand how an organism made of a single cell "decides" to swim toward a light source, and found that it reacts within half a millisecond. He proposed that one single protein was both capturing the light and acting as an ion channel, a passage that lets electrically charged particles cross the cell membrane.

Nagel, a specialist in ion channels, put the hypothesis to the test by injecting Chlamydomonas genes into frog eggs. That is how channelrhodopsin-2 was identified, a channel that opens when exposed to light. In 2003 the two published a study showing the protein could be introduced into human and hamster cells to generate electrical impulses by light.

Deisseroth took it to nerve cells. In 2005 he introduced the gene into neurons of rats and triggered a nerve signal by shining blue light on them. The method got the name optogenetics the following year. In 2007 he made the switch work inside the brain of living mice: with light delivered through an optical fibre, he controlled the movement of the animals' whiskers.

"It all started with a seemingly simple question: how does a microscopic alga know how to swim toward light? Nobody there was looking for a treatment for any disease," said Victor Santos, a neuroscientist and professor at the Federal University of Minas Gerais, in comments published by the Brazilian news site g1.

Why this changed neuroscience

The problem optogenetics solved was not a lack of data about the brain. It was a lack of proof.

"Until the early 2000s, much of neuroscience depended on correlations: we saw a region activate during a behaviour, but it was hard to prove it was the cause," Santos told the Brazilian magazine Veja. The available tools worked against that. Electrical stimulation, for example, could reach different cells and structures at once, which made it hard to know which of them was related to a given function.

"Optogenetics changed that scenario. It allows us to activate or inhibit specific populations of neurons with temporal and cellular precision, including in animals during behaviour, making it possible to test relations between the activity of neural circuits and functions such as memory, fear and reward," said Cristiane Furini, a neuroscientist and professor at the Pontifical Catholic University of Rio Grande do Sul and an affiliate member of the Brazilian Academy of Sciences.

One illustration of what that allows: in 2012, Deisseroth and Susumu Tonegawa reactivated cells associated with a fear memory in mice, showing which neurons took part specifically in that recollection.

What reaches patients, and what does not

Most of what has been learned with the technique came from experiments in animals. Turning it into human treatment involves two additional problems: getting the light-sensitive protein into the intended cells, and getting light to tissue inside the body.

The most advanced clinical front is vision. In retinitis pigmentosa, a degenerative disease that progressively destroys the retina's photoreceptor cells, the strategy is to make other retinal cells sensitive to light so they can send signals to the brain in place of the dead ones. According to Folha de S.Paulo, this is already in first-phase clinical trials, and early results show recovery of some light-sensitive abilities. Researchers also hope optogenetics can improve cochlear implants, the electronic devices used in severe hearing loss, by allowing more precise stimulation of the auditory nerve than current electrical devices.

Beyond that, the picture is research, not therapy. The Nobel does not mean that controlling neurons with light is an available treatment for Parkinson's disease, Alzheimer's or depression. In epilepsy, Santos says, animal experiments have already interrupted seizures by silencing, at the right place and the right moment, the neurons that trigger them, and that this knowledge guides the development of new drugs and the refinement of existing therapies such as deep brain stimulation.

"What we are doing now, and many others too, is figuring out how we can harness this precision to find new treatments, new drugs and new neuromodulation approaches that build on this foundation of causality," Deisseroth told the magazine Scientific American.

What is known, and what is still unknown

What is established: the mechanism is described and reproducible. Blue light opens a channel in the channelrhodopsin protein, ions enter the cell and an electrical impulse is produced, and whatever cell receives the protein becomes sensitive to light. The method is used in laboratories worldwide, it has made it possible to test cause and effect between specific circuits and behaviours in living animals, and there are clinical studies under way using it to restore part of the vision of people with degenerative retinal disease.

What remains open: whether and when this becomes treatment for neurological and psychiatric conditions. "In the clinic we are still at the beginning, and caution is needed," Santos said. "The challenge is getting the gene and the light to the cells safely, which takes time and a lot of testing." The same researcher frames what has already been delivered in different terms: "The greatest gift of this discovery is already here. It gave us a causal map of the brain. And it is from that knowledge that the therapies of the future will be born."

Abdel El Manira, a professor at the Karolinska Institute, said optogenetics has produced extraordinary advances for neuroscience, and added that "the brain still holds countless mysteries, with much more to learn and discover."