By Talitha Smith
“It was one of those moments where I can remember the time and the date and the room I was in.”
On the afternoon of 12 June 1999, a Saturday, Gero Miesenböck returned to his apartment in Manhattan from a long walk after lunch, ready to open a book he had been absorbed in, Independence Day by Richard Ford. “As I was reaching for the book, drifting from the real world into Ford’s fictional New Jersey, there was the idea of optogenetic control. I knew instantly that I was on to something. My wife remembers my excitement as I tried to explain the concept to her, and especially the terrible hangover nearly two years later when my postdoc and I celebrated that we had got it to work.”
That Manhattan moment launched a series of now classical studies that made Miesenböck the first scientist to modify nerve cells genetically so that their activity could be controlled by light. This breakthrough technology, called optogenetics, has transformed neuroscientific research and opened new possibilities for the treatment of brain disorders. By providing the means to control neural signals with high precision, optogenetics has raised neurobiology’s standards of proof. It has shed light, literally and figuratively, on virtually every brain function: sensation and movement, motivation and learning, sleep and waking, communication and decision-making.
“If you want to claim that you understand how the brain gives rise to perception, action, emotion or thought, show me that you can switch on fear, recall a memory, bias a decision or induce sleep by manipulating the physical state of the brain,” says Miesenböck, now the Waynflete Professor of Physiology and Director of the Centre for Neural Circuits and Behaviour at Oxford University’s Department of Physiology, Anatomy and Genetics. Conventional brain stimulation techniques are inadequate for this purpose because of the overlapping activation of many different, densely intermingled neurons with diverse and opposing effects.
In a landmark paper published in January 2002, Miesenböck offered a solution to the challenge of manipulating well-defined neuronal populations in the intact brain. Writing in the journal Neuron, he drew an analogy with a radio broadcast that can be heard only by those with a correctly tuned set: “The method uses a broadly transmitted optical signal that can be decoded and transduced into electrical activity by only a subset of all illuminated neurons. The ‘receiver’ of the optical signal is encoded in DNA, and the responsive subset of neurons can therefore be restricted genetically to certain cell types or circuit elements.” Twenty years later, scientists around the world rely on this principle to gain a deeper understanding of how the brain works.
Back in the summer of 1999, though, Miesenböck had just begun his independent research career as tenure-track faculty at Memorial Sloan-Kettering Cancer Center and Cornell University. Before then, he had been a postdoctoral scientist in a leading cell biology lab, run by the future Nobel laureate James Rothman. “I had seen that to dissect a complex biological mechanism and work out cause and effect, it is essential to be able to control the process.” But in neuroscience, Miesenböck felt there was still too much observation and too little intervention, in effect limiting how much we could learn.
His postdoctoral project had involved engineering neurons genetically so that they would emit light when information passed between them. These studies were in the back of his mind when the optogenetics idea struck. “I thought, wouldn’t it be wonderful if the two ingredients that I had relied on in my earlier work — genetics and optics — could be combined again, but this time for the opposite way of communicating with the neuron: not the neuron telling us but we telling it what to do?”
Shortly after his research group had set out to turn the idea into a reality, Francis Crick, of DNA double-helix fame, published an article titled ‘The Impact of Molecular Biology on Neuroscience’ in the millennial issue of Philosophical Transactions of the Royal Society. Miesenböck was astonished to read the following passage: “The next requirement [for understanding the brain] is to be able to turn the firing of one or more types of neuron on or off in a rapid manner in the behaving animal. The ideal signal would be light. This seems rather far-fetched but it is conceivable that molecular biologists could engineer a particular cell type to be sensitive to light in this way.” Miesenböck wrote to Crick to tell him that his team were already working on the problem, and Crick asked to be kept informed of their progress.
In January 2002, the team reported the first demonstration of optogenetic control of neural activity. They had transplanted, via genetic modification, light-sensing proteins from the eye (called rhodopsins) into nerve cells. Shining light on these genetically modified nerve cells caused them to fire electrical impulses. Crick received a copy of the manuscript before publication and responded with delight.
The next key achievement for Miesenböck’s team was a first demonstration of the optogenetic control of animal behaviour, reported in April 2005 in Cell. An optogenetic sex swap followed in 2008 and the optogenetic implantation of an artificial memory in 2009. These studies revealed biological mechanisms beyond the reach of prior methods: a hidden capacity for male behaviour (and strategies for its suppression) in the female nervous system, and the identity of the inner critic that allows animals to learn from the consequences of their actions.
Miesenböck’s foundational studies led to an explosion in optogenetic applications and technical improvements. In two independent publications in the second half of 2005, the groups of Karl Deisseroth and Stefan Herlitze found that exchanging Miesenböck’s rhodopsin for a photopigment called channelrhodopsin-2 resulted in a simpler-to-use and more effective technology. The gene encoding channelrhodopsin-2 had been discovered in 2003, through an initially unrelated line of research into light-responsive algae by Peter Hegemann.
Today, serious efforts have begun to use optogenetics to replace neural signals lost to injury or disease. Clinical trials to restore vision in humans with retinal degeneration are under way, and experimental treatments for a range of conditions, from Parkinson’s disease to urinary incontinence and chronic pain, are in active development.
“With all the current hype,” says Miesenböck, “it may seem unimaginable that the early papers were very difficult to publish. As Steve Jobs famously said, people don’t know what they want or need until you put it in front of them, and even then innovation isn’t always embraced. One anonymous reviewer of our very first manuscript suggested that we should study the retina instead, ‘which conveniently has light-sensitive cells already built in’. I hope that reviewer sees our point now.”
Professor Gero Miesenböck is the recipient of the 2019 Warren Alpert Foundation Prize for seminal discoveries in optogenetics.
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