Gero Miesenböck
Waynflete Professor of Physiology, University of Oxford Director, Centre for Neural Circuits and Behaviour

https://doi.org/10.36866/pn.93.45

What led you to physiology?

I had a circuitous route into physiology. I studied medicine in Austria – where I’m from – but discovered early on that clinical medicine and I were not made for each other. I liked the basic science subjects but got bored in the clinic. I also realised that being able to repeat a failed experiment is a good thing. So I did research as a medical student on lipoprotein metabolism, came across Goldstein and Brown’s work on receptor-mediated endocytosis and became fascinated by cellular membrane trafficking. This led me to do a post-doc with Jim Rothman, who was just today announced as a winner of this year’s Nobel Prize in Physiology or Medicine. I initially worked on a cell biological problem in his lab but later began to develop genetically encoded optical reporters for imaging synaptic transmission. The combination of genetics and optics has been a recurring methodological theme ever since.

What inspired you to create optogenetics?

I had worked on genetically encoded fluorescent proteins and engineered them to make neuronal activity visible. Optogenetics, as it’s now understood in its narrow sense, is communication in the opposite direction: you don’t make neuronal activity visible, you use light to elicit or suppress it.

I was steeped in thinking about optically active proteins and neurons but wasn’t actively trying to invent optogenetic control when I had the idea. It was a Saturday, I was at home and drifting back into a novel I was reading, and suddenly I thought, ‘Wouldn’t it be amazing if one could invert the direction of optical communication with the brain. Use light not just to observe, but also to control.’ As soon as I had the idea I realised that if it worked it would have a major impact.

It was a high risk thing; it was by no means clear that it would work. There were many improvements that came after our initial proof-of-concept experiments, and these improvements contributed to the rapid spread of the technique. Needless to say not all of the improvements are ours – a few people have made important contributions. It’s been more than 10 years since we reported the fundamental concept of optogenetic control: the idea of putting a photoreceptor like rhodopsin into a neuron in order to control its activity with light. Like all these things, it started slowly with just my lab. In 2005 we showed we could remote-control the behaviour of an animal – that was another milestone that began to capture people’s imagination. A few months later channelrhodopsin was substituted for the rhodopsin we had initially used. This improvement made the whole approach much simpler to use, and the field exploded.

What is it like to lead a team whose work is receiving so much attention?

You don’t think about the attention of others when you try to solve a problem – it was never on the forefront of my mind. I’m captivated by the scientific question at hand. The driver behind all of it was curiosity about how the nervous system works rather than a desire to push methodologies. The biological problem still remains what I find the most stimulating.

What are the most important doors that optogenetics will continue to open within research?

Our very first paper ended with two short paragraphs outlining what might become possible, in vitro and in vivo. These paragraphs contain, in a nutshell, an accurate prediction of how the field has developed. In vitro, you can take an explanted piece of brain tissue, such as a brain slice, and reconnect it to artificial inputs that have physiological relevance. You can literally talk to a piece of brain tissue in the controlled setting of a dish. This is something that just hadn’t been possible as long as the senses were the only portals of communication with someone else’s brain. Perhaps the most straightforward example of such an in vitro experiment is the mapping of functional connectivity by putting a listening post – be that a fluorescent dye or an electrode – into one cell and then probing around quickly with a laser beam to get a picture of which cells communicate with the target.

In vivo, the key approach that optogenetics has enabled is to pinpoint the neuronal substrates of behaviour more precisely and directly than before. Neuroscientists can finally perform reconstitution experiments – something that geneticists and biochemists have been able to do for a long time. You have to ask yourself what reconstitution would entail in neuroscience. You can’t just take a brain, grind it up, purify the components and put them back together. But what reconstitution can be is taking pure activity patterns, playing them back to the intact nervous system and seeing whether you can elicit a specific behaviour. That’s something that was possible only to a very limited extent before optogenetics, but that we can do now.

The other thing that optogenetics has allowed us to do is to skip all the peripheral processes. In the past, if you were a neurophysiologist you would usually go about probing the brain by showing an animal something on a screen, giving it something to smell or playing some tones for it to listen to. Your approach to the neural circuitry behind the senses was always indirect; the senses were the gatekeepers that would determine the kind of information you could feed into the brain, and you couldn’t be sure what you were supplying. With optogenetics, you can jump right into the middle of a circuit, which I think has also been a great, great advance.

What do you think will be the most important therapeutic applications for optogenetics?

The most immediate and obvious area where optogenetics can probably help is visual restoration. If you have damage to or degeneration of your photoreceptors, you might restore light sensitivity to other neurons in the retina – this might bring back a significant amount of vision. I think the advantage of focusing on the retina first is that the problem of delivering a foreign gene and expressing a foreign protein is less acute because the eye is a privileged compartment both in terms of access and also immunologically. For this and all other applications of optogenetics, a genetic modification is a key requirement. So while our flies and other people’s mice don’t mind, I think most humans still do!

Do you think that there is a risk of the technique being abused?

I think the potential for abuse is there with many medical advances. There’s often a narrow line between what’s beneficial and what’s potentially dangerous. That said, I don’t think that things like mind control of people or the use of remote-controlled animals as weapons is something that’s anywhere around the corner. We simply don’t know enough about the basic neurobiology of the processes that would be involved. If we understood completely how, for instance, a fly navigates its environment, selects a target, hovers, and perhaps lands and takes off again, we would be very happy campers, but we don’t know any of this. When our paper on optogenetically controlled flies appeared in 2005, an American journalist called and asked me: ‘So when are we going to invade another country with an army of remote-controlled flies?’ The answer was then, as it is now: ‘Not any time soon.’

What are the next steps for optogenetics?

I think there is significant development that needs to happen on the optical side of things. In most experiments light is delivered by relatively simple means. You just either shine light onto an entire animal, as we do with our fruit flies, or you insert a fibreoptic cable into certain nuclei in the brain and illuminate these areas completely. But in many cases I think it would be really nice to be able to control the members of a population of neurons independently, and also to have some kind of direct read-out of what the individual nerve cells are actually doing. Are they obeying our optogenetic commands or just rolling their eyes and doing what they feel like, like sullen teenagers? To find out would be a huge technical challenge, one I don’t even know how to begin to address. But if we could there’s a whole range of basic science questions that would open up, including clever ways of feedback control.

Another area of great difficulty and promise is in the genetic targeting of cells. One of the key innovations of optogenetics is to use genetic address labels in order to single out specific neurons in the brain like needles in a haystack. But it turns out that most of the address labels we currently use are not sufficiently precise. Our addresses often consist only of the name of a town or county, when in reality we would like to direct our optical messages to individual houses in a town or specific inhabitants in a house. To develop a genetic postcode that would allow us to do this in a systematic fashion would be a real breakthrough.

What is the next big thing for you?

We are after the elementary logic of information processing in the brain. Although much of this work is done by studying particular behaviours in fruit flies, we don’t care all that much about these behaviours or the fact that they occur in flies. Rather, our research is motivated by the belief that animals do not employ an endless variety of brain circuits, but a limited set: circuits that compare signals, apply thresholds, integrate information, keep time, store memories. We approach these circuits by studying particular behaviours in the fly, but the goal is always general – we just use these particular behaviours and this particular organism to get at things that we believe are fundamental to all brain function. Some of the circuits that we are especially interested in at the moment are those that keep track of events over longer time scales: circuits that can take information and not respond instantly like a reflex arc, but that actually hold and weigh and ponder the information over extended periods of time.

We also have some other techniques that we are developing, but these are of course still trade secrets!

Further information

Gero’s talk on re-engineering the brain: www.ted.com/talks/gero_miesenboeck.html
Centre for Neural Circuits and Behaviour: www.cncb.ox.ac.uk