Waynflete Professor of Physiology, Wellcome Investigator
Gero Miesenböck studied medicine at the University of Innsbruck in his native Austria and did postdoctoral research at Memorial Sloan-Kettering Cancer Center in New York. He was on the faculty of Memorial Sloan-Kettering Cancer Center and Yale University before coming to Oxford in 2007. Gero is the founding director of the CNCB.
Gero has invented and developed many of the optogenetic techniques used for visualizing and controlling nerve cells with light. He has also been a pioneer in the use of flies to study neural circuits.
As the current Waynflete Professor of Physiology do you feel that you are part of a tradition?
When I arrived in Oxford, my lab was housed in the Sherrington Building, named after perhaps the most famous Waynflete Professor of Physiology. In 1937, Charles Sherrington described the brain as 'an enchanted loom where millions of flashing shuttles weave a dissolving pattern, always a meaningful pattern though never an abiding one; a shifting harmony of subpatterns.' Despite the Victorian prose, Sherrington's vision of flashes of light signalling the activity of nerve cells contains a modern idea: that the brain could reveal its inner workings optically. Many of the technical aspects of my work revolve around this idea.
It's interesting that, as an avowed reductionist, you should start with the poetic.
Good poetry is also reductionist: it makes complex thought or sentiment elemental. I in fact wanted to become a writer for a very long time. My father was a classicist, and I was tempted to follow him into literature. But he was frustrated with his chosen profession, its subjective standards and its limited potential for discovery. He persuaded me, in strong terms, to choose science as the more exciting path. I started reading more and more science when I was at school and I became gripped by it. But I was gripped from an abstract point of view; I liked ideas and the way they were expressed and tested. I wasn't tinkering around with a chemistry set.
Your father was clearly an early mentor. Were there others?
In 1989, I spent three months at the University of Umeå, near the Arctic Circle, to learn an experimental technique I needed for my dissertation. Unwisely, I had chosen winter for my visit. In the near-complete darkness of northern Sweden, our circadian clocks started to run free. People worked the strangest hours because it didn't matter when you went to bed or got up: it was nearly always dark. The only event that brought everyone together was our journal club—a weekly discussion of the scientific literature that is a fixture in many labs. There I came across papers that blew me away with their boldness and the beauty of their ideas. The papers were the work of James Rothman. I made up my mind right there that I wanted a postdoctoral position with Rothman.
So how did you get yourself out of Austria and over to America?
I wrote to Rothman a year or two later when I was finishing medical school. It didn't take long until a rejection letter arrived, in which my surname was spectacularly misspelled. Admittedly it is an unusual name, but 4 out of the 10 letters were incorrect. Come on! But I persisted. I visited Felix Wieland, a collaborator of Rothman's in Heidelberg, and he must have put in a word for me, because a few days later I got a phone call at midnight, and it was Rothman saying that he might have made a mistake. In 1992 I moved to the USA for what I thought would be two or three years and ended up staying for 15. Rothman took a risk on a complete unknown. I try to remember this nowadays when I get applications that seem to come out of nowhere, but may in fact be the result of years of reflection and preparation.
What was your first project in the Rothman lab?
I initially worked on protein sorting in cells. But soon my work concentrated on what has become a recurring theme: the development of biological tools to illuminate biological problems. The first such tool used a light-emitting protein to make communication between nerve cells visible. To get the system to work, I had to isolate the DNA that encodes the protein from a particular species of shrimp found along the south coast of Japan. But getting my hands on these shrimp proved difficult. Late every evening in New York, I asked a Japanese colleague to make phone calls to universities, aquariums and natural history museums in Japan, but no luck. Finally, I just rang the Marine Biological Laboratory in Woods Hole, Massachusetts, and asked to speak to their bioluminescence expert, fully expecting to be told to get lost. But incredibly, the phone operator knew how to field my request. I was asked to hold on for a moment and then a voice came on the line. It was Osamu Shimomura. By chance I found myself talking to the one man who could help me.
Osamu Shimomura won the Nobel Prize in 2008 for his discovery of the green fluorescent protein (GFP), an essential reagent in biology. GFP glows greenly when exposed to blue light. It was first purified and studied by Shimomura in the 60s and 70s.
I explained the shrimp situation to him and he sent me a sample he had collected and sun-dried in Japan in 1944, along with a stack of reprints. One of these reprints had a stunning cover photograph: a manuscript page reporting the structure of the shrimp's light-emitting chemical. The page was illuminated by the chemical reaction described on it—a little like Escher's famous lithograph of hands drawing themselves.
Although Shimomura's shrimp proved completely useless, they are one of my prized possessions. The light-generating system is still well enough preserved that you can see a beautiful, eerie blue glow when you crush a few shrimp and add water. The genetic material, of course, was degraded, but Shimomura directed me to a fresh supply of shrimp, from which I managed to isolate a piece of DNA encoding the glowing enzyme. It was this enzyme that produced the first images of synaptic transmission: Sherrington's weaving shuttles. A later incarnation of the same principle, termed synapto-pHluorin, drew directly on Shimomura's discovery of GFP. It used a pH-sensitive GFP mutant to provide an optical report of communication between neurons.
What was your first project in your own lab?
The initial aim was to image information flow in a neural circuit with synapto-pHluorin. But then very quickly, in the summer of 1999—it was one of those moments where I can even remember the time and the date and the room I was in—I had the idea of using light not only to observe but also to control. That then quickly became another focus of the lab.
When was that, and where were you?
It was the late afternoon of June 12, 1999, a Saturday. We were living on Union Square in Manhattan at the time. I had taken a long walk after lunch, come back home, and stretched out on the bed, ready to return to a book I was 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.
Where did the remote control idea come from?
I guess I had the advantage of being a newcomer to neurobiology. I was not too weighed down by received wisdom, maybe not too weighed down by neuroscience knowledge in general. But I had worked in a leading cell biology lab. I had seen that to establish causality and dissect a complex mechanism it's essential to be able to control it. In neuroscience, I felt there was still way too much observation and not enough intervention. So I thought, wouldn't it be wonderful if the two ingredients that I had relied on in my work with synapto-pHluorin—genetics and optics—could be combined again but this time for the opposite way of communicating with the neuron.
At first we were completely alone doing this work. Now, of course, many people have adopted and also improved the approach.
With optogenetic remote control you can say that neuron X is important for behaviour Y. What other questions can you address?
There is a whole range of questions we can ask when we have the ability to control specific groups of neurons. Optogenetics allows us to make non-invasive and physiological connections to brain tissue. We can use these techniques to work out the wiring diagrams of neural circuits. We can apply spatiotemporal patterns of input activity and measure what kinds of signals a target cell or a group of target cells is looking for. It means that rather than just finding the anatomical connections between neurons we can deduce the input/output characteristics of a circuit. A still higher level of analysis is to see what exact features of activity patterns are relevant for perception, action, cognition, memory and so forth.
Have you always been attracted to technological solutions and inventing new methods?
It was not a deliberate choice. I wanted to do certain types of experiment, and I couldn't make any progress until I developed what was necessary. I wanted to work on networks of neurons and it was clear that there needed to be a new way of interacting with them.
Also, there is beauty in these developmental efforts in their own right. It's really a pleasure to see something through from the conceptual stage, to trying to get it work, and then actually using it. Seeing the first images of a fruit fly smelling an odour as revealed by synapto-pHluorin and looking back over the entire arc that began with the engineering of the GFP mutant, or seeing the first remote-controlled fly take flight at the flash of a laser beam, I have to say these were very satisfying moments.
Why did you choose to work on the fly?
The nematode C elegans has just 302 neurons and a correspondingly, shall we say, basic behavioural repertoire. Rodents are too complex. If you look at a mouse brain under a microscope you instantly realise that you are seeing only a small part of a much bigger structure. In contrast, if you look at a fly brain under a microscope you get the impression that you are seeing something self-contained. Most of the relevant parts are there, visible at once. The scale of the biological structure and that of our analytical methods, which operate at the resolution of individual cells, matches. Then there are the added benefits: a century of genetic work has been done on the fly, and its behaviour is rich.
But it is easy to underestimate the complexity of even the most simple-seeming organisms. In his late years Francis Crick, co-discoverer of the structure of DNA, became interested in consciousness. Crick once said to Seymour Benzer that he didn't think the fly was very interesting from the point of view of consciousness, to which Benzer responded—I don't recall the exact words, but it went something like "Francis, don't underestimate flies; they can do more than you can do: For example, can you fly away and land upside down on the ceiling?"
What are your favourite papers?
There's of course the one discussed in that fateful journal club in Umeå: "The rate of bulk flow from the endoplasmic reticulum to the cell surface" by Felix Wieland, Michael Gleason, Tito Serafini, and Jim Rothman (Cell 1987: 50, 289-300).
Another eye-opener was "The statistical nature of the acetycholine potential and its molecular components" by Bernard Katz and Ricardo Miledi (J. Physiol. 1972: 224, 665-699). This paper is a fine example of how much you can learn from your data if you have the courage to guess the underlying mechanism and the mathematical chops to formalise your guess. Chuck Stevens's work is also an inspiration in this regard.
And which of your own papers are you particularly fond of?
Well, there's the two that laid the foundations of optogenetic control: "Selective photostimulation of genetically chARGed neurons" with Boris Zemelman, Georgia Lee and Minna Ng (Neuron 2002: 33, 15-22), and "Remote control of behavior through genetically targeted photostimulation of neurons" with Susana Lima (Cell 2005: 121, 141-152).
Perhaps because I love literature, I tend to agonize over my own writing. I'm rather slow, managing at most 500 words a day even if I do nothing but write. But there was one paper, a story of optogenetically switched sexual identities, that virtually wrote itself on a single Sunday: "Sex-specific control and tuning of the pattern generator for courtship song in Drosophila" with Dylan Clyne (Cell 2008: 133, 354-363). These are some of the most fun experiments we've ever done.
You take a top-down, reductionist approach in your work. Why?
Our goal is to understand the cellular basis of behaviour. There are two ways of approaching the problem: from the bottom up, or from the top down. If you start from the bottom up, by studying individual cells and their interactions, you quickly run into a problem: there is a horizon of predictability beyond which you cannot see. Even if you understand each individual component and each pairwise interaction in great detail, put just a few of these components together and you'll discover that you can't make any predictions at all about the behaviour of the resulting system. The problem is not particular to neuroscience or biology. A famous example is the three-body problem in celestial mechanics. Poincaré showed that the motion of a system of orbiting masses governed by precise Newtonian laws gives rise to deterministic chaos if there are more than two masses involved. So if someone tells me they are going to embark on a massive project in which they will analyse every neuron and every connection in the brain and then model the whole thing in a computer and find out how it works, well good luck but I won't be closing down my lab just yet.
So what's the alternative?
Given this horizon of predictability from the bottom up, the rational approach would seem to start from the top down. Find an interesting behaviour that taxes a particular circuit, and then take the system apart. Much of our work is predicated on the belief that brains do not employ an endless variety of circuits but rather a limited set. You need circuits that can compare signals, apply thresholds, or integrate information. You need oscillators to keep time, you need buffers that can hold the intermediates of your computations, you need memory you can write to and read from, and so on. If you understand any one of these circuits in any behavioural context, chances are you have learned something general.
It is sometimes said that the greatest challenge for science in the 21st century is to understand consciousness in biological terms. Would you agree?
I disagree. Some days I think consciousness is impossible to grasp, and other days that it is trivial. But I do believe that it is purely a product of our nervous system, and that there are no special laws of nature required to explain it. Perhaps the conscious self is an illusion that the brain creates that makes us think that someone is home, when in reality there is no one home. I don't think this is a depressing outlook, on the contrary I find it exhilarating. The conscious self is like an elegant, efficiently designed interface on a computer: a simple clean unified view of yourself that hides the mess of wires underneath. But now I'm going out on a limb. I'm not sure I'm even making sense.
What brought you to Oxford?
After New York I went to Yale. But after a couple of years I was approached by Oxford, and my first thought was, No way! I had spent a month in England as a boy, sent to Bournemouth for elocution lessons. As you can hear, they were not successful. I was bored and homesick and vowed I would never visit this country again. I kept to my promise for 30 years, but my wife persuaded me that I should at least consider the job. And surprisingly, I find that I love it here.