Each year I like to document the Nobel Prize in Physiology or Medicine here on SBM – it’s a great reminder of the power of science to transform medicine. There is nothing like it in so-called “alternative medicine”, which is still peddling basically the same snake oil and energy nonsense of previous centuries, just with updated marketing. This year the prize goes to Karl Deisseroth, Peter Hegemann, and Georg Nagel for their work developing optogenetics. This is a great story about a powerful tool that allows us to create a functional map of the brain.
The story begins with Hegemann, who in the 1990s was studying the free-swimming algae, Chlamydomonas. The algae swim towards light, which anyone can reproduce by shining a light on a petri dish full of the green organisms. They have a small eyespot that can detect light, but Hegemann was fascinated with how quickly they were able to respond to a light signal. This led him to hypothesize that the algae may be using a different method for turning light into a signal that can affect their behavior than vertebrate eyes.
In vertebrate eyes there is a cascade of events, called phototransduction, starting with a photon of light hitting 11-cis-retinal attached to an opsin protein in cones and rhodopsin in rods. This causes a conformational change in the retinal, which activates the opsin, which activates G-protein transducin, causing its α-subunit to exchange GDP for GTP. Transducin then activates phosphodiesterase-6 (PDE6), which hydrolyzes cGMP, lowering its cytoplasmic level. This causes cGMP-gated Na⁺/Ca²⁺ channels to close, reducing the inward “dark current.” This causes the photoreceptor to hyperpolarize, reducing Ca²⁺ entry at the synaptic terminal and therefore reduces glutamate release onto bipolar cells.
Don’t worry about all those details – the point is, this takes time, 100-200 ms. When Hegemann attached electrodes to Chlamydomonas and shined a light on them, he was able to detect an electrical signal in half a millisecond – incredibly fast. This is simply too fast for anything like phototransduction, so he thought perhaps it must be the same protein that detects the light and creates the resulting electrical pulse. Now all he had to do was identify that protein.
A Japanese group had already mapped the DNA of Chlamydomonas and, of the genes identified, two had properties that might fit the bill. But this was now a bit out of the field of expertise of Hegemann, so he contacted Nagel for help and sent him the code for the two candidate genes. Nagel injected the genes into separate batches of frog eggs, which began to express the proteins. He could then study how the proteins functioned and was able to confirm Hegemann’s hypothesis. Both proteins, named channelrhodopsin-1 and channelrhodopsin-2, were ion channels that respond to light by opening up, allowing positive ions to flow through, and creating an electrical potential. Channelrhodopsin-2 was particularly powerful, creating an electrical signal in 0.2 milliseconds. They were able to incorporate the gene for this protein into human and hamster kidney cells and show that they become light sensitive.
This is where Deisseroth enters the picture. He is a physician and neuroscientist studying mental illness like schizophrenia. His early work in neuroanatomy was interesting, but he realized he needed a functional map of the brain if he was going to make real progress understanding these illnesses and conditions. He searched for a method to activate on demand a signal brain neuron, so that its connections and effects could then be studied and mapped. He heard about the work of Hegemman and Nagel and asked Nagel for the DNA of the Channelrhodopsin-2 protein, which he provided. Deisseroth started by incorporating the gene into rat neurons cultivated in a petri dish. At first he was concerned that introducing a foreign protein into the neurons might cause some injury, but they did fine. When Deisseroth exposed the modified rat neurons to light, they responded immediately by generating an electrical signal that could be propagated to other neurons. This was just the beginning of the work, however.
Deisseroth began to collaborate with Hegemann and Nagel and also other groups to develop this into a useful lab technique. They were able to identify other light-sensitive proteins, responding to different wavelengths of light. They were also able to genetically modify mice so that their neurons produced one of these proteins. In fact, they could do so for just one specific population of neurons. They then introduce a thin optic fiber into the brain of such a mouse – and now they have a switch they can use to activate those specific neurons. In some of his early work with this technique, Deisseroth was able to determine which neurons control the mouse whiskers, and also another group of neurons that wake up sleeping mice.
And with this work, the field of optogenetics was established. Now neuroscientists can tag specific neurons in living animals and then activate them at will, exploring the specific effects of these neurons in the living brain. This allows neuroscientists to develop a detailed functional map of the brain, and to test many hypotheses. The Nobel committee considers this a “transformative” technology for neuroscience, and I agree.
I also always like to use the Nobel prizes as an opportunity to highlight how cutting-edge science today is such a collaborative and often international effort. They can only give the prize to three individuals, and the three winners were clearly at the center of this advance. But they relied upon the work of other scientists from around the world, and collaborated with many people not only at their own institutions but in many others. This kind of research would not have been possible for a single team at a single university.
