November 1, 2016 (Vol. 36, No. 19)

Vicki Glaser Writer GEN

It’s Important, Says Optogenetics Pioneer, to Keep a Laser Focus on Neuronal Circuits

If you want to experience bursts of illumination on the subject of optogenetic control, you should have a conversation with Gero Miesenböck, M.D., the first scientist to genetically engineer light sensitivity into neurons. Failing that, you should try the next best thing: read this interview, which GEN presents as part of its 35th anniversary celebrations.

At present, Dr. Miesenböck is director of the Centre for Neural Circuits and Behaviour at the University of Oxford. Since he published a 2002 paper that laid the foundations of optogenetic control (“Selective photostimulation of genetically chARGed neurons,” in Neuron), he has been refining his optogenetic techniques, applying them in studies designed to isolate and characterize discrete bits of brain circuitry, and amassing an impressive collection of awards and professional honors. For example, Dr. Miesenböck won the Brain Prize in 2013, and he was elected a fellow of the Royal Society in 2015. More recently (last August), he won the Massry Prize.

Besides contributing foundational work on the optogenetics technique, Dr. Miesenböck has been a leader in applying optogenetics as a means of influencing the function of nerve cells remotely, using flashes of light instead of direct electrical connections. In fact, Dr. Miesenböck was the first to use optogenetics to remote-control the behavior of an animal, which he had bred to contain light-sensitive nerve cells in its brain.

As this interview reveals, Dr. Miesenböck favors a top-down, piecemeal, reductive approach to the study of the brain’s circuitry. For a contrasting approach, one that involves analyzing every neuron and every connection in the brain, and then using a computer to model the whole ensemble, GEN’s readers will want to consult another feature in this issue, “Toward Troubleshooting the Connectome.”

GEN: Please briefly describe the basic principles behind optogenetics, which uses light to turn nerve cells on and off selectively — a method that you pioneered and has revolutionized the field of brain research.

Dr. Miesenböck: The name “optogenetics” is a little misleading because it suggests a method for controlling gene function with light. That’s incorrect. Optogenetics is all about controlling cells, not genes. Optogenetic techniques allow neuroscientists to write or edit patterns of neuronal activity in the living brain with cellular and molecular specificity.

The key reagents to do this are light-responsive proteins that modulate the electrical signals with which nerve cells communicate. Such proteins, termed opsins, are found naturally in photoreceptor cells. Photoreceptors respond to light by generating electrical signals—in animals, this is the beginning of the process by which the brain transforms light detected by the eye into an internal representation of the visible world. Optogenetics borrows the genes encoding these light-responsive proteins and transplants them genetically to cells that are not normally light sensitive.

Optogenetic control is thus a form of wireless communication in which the receiver of the wireless signal is fabricated from materials encoded in DNA. Each nerve cell that switches on some specified gene linked to the identity of the cell will at the same time produce a light-responsive protein. The activity of that cell can then be controlled simply by turning on an external light source, without any undesired cross-talk to neighboring cells that lack the receiver.

We first demonstrated the principle of optogenetic control, using an ectopically expressed opsin as the light sensor, in a paper published in January 2002; the same study also showed that genetically targeting the light-sensing mechanism allowed one to control specific neuronal populations. A paper published in April 2005 showed that optogenetic activation of different circuits in the brain could change specific aspects of an animal’s behavior. These studies thus established all the fundamental concepts of optogenetics.

GEN: Much of your research on understanding the role of specific brain circuits and characterizing neural networks, beginning when you were at Memorial Sloan-Kettering Cancer Center and Yale University, and continuing now at the University of Oxford, has involved Drosophila and then progressed to mice as well. How is the technique being applied to human brain research?

Dr. Miesenböck: I disagree with the premise that my work has “progressed” from flies to mice. In fact, after a little dabbling in mice, my lab has “regressed.” We are now once again focusing exclusively on Drosophila.

If anything, the short experience of studying mice has reinforced my commitment to the fly. Why? Because the numerically simpler brain of the fly, with its about 100,000 neurons, allows much deeper insights into how the nervous system works. It becomes possible to link higher brain functions—say, a cognitive process like the decision to pursue a particular course of action—pretty seamlessly to physical events in identified neurons, and to the molecular machinery that underpins the function of these neurons.

Our ambition is to exorcise vague psychological notions and replace them with biophysical principles. We feel that the odds of succeeding in this ambition are most favorable in the fly. These animals are smart enough to do really interesting things, and yet they accomplish them with brains simple enough to give us hope that one day we will understand them.

And, of course, biological mechanisms are conserved across evolution. Once nature has hit on a particular solution to a particular problem, this solution tends to get used again and again. So I think we all have a little bit of fly in us.

A beam of light selectively activates a group of dopamine-producing neurons in the brain of a fly.

GEN: How is—and how in the future do you expect—optogenetics to impact human health and the development of new therapeutic approaches for diseases such as blindness, Parkinson’s disease, Alzheimer’s disease, and addiction, for example?

Dr. Miesenböck: There are two principal ways in which optogenetics can contribute to human health. The first is in the discovery of new targets for conventional drugs: if optogenetic manipulations of cell groups X, Y, and Z cause an animal to eat, sleep, or throw caution in the wind, then X, Y, and Z are flagged as potential targets for medicines against obesity, insomnia, and anxiety, respectively. Focusing the drug discovery process on molecular targets that are unique to the neurons that matter—X, Y, and Z—may well lead to therapies for new indications, or to cleaner and more effective drugs for existing ones.

Then there is the potential for direct applications of optogenetic technologies in humans. There are three issues to consider here. The first is legal or ethical: Is it okay to interfere with someone else’s brain? Frankly, I think there is no qualitative difference between physical means for influencing brain function, such as optogenetics, and chemical manipulations, be they psychoactive pharmaceuticals or the cocktail that helps you unwind after a difficult day.

The second issue is technical. Optogenetics requires the introduction of a foreign gene—encoding a light-responsive protein—into the brain. This is a form of gene therapy, but with the important difference that the gene being introduced is not a correct copy of a defective human gene that needs to be repaired. It is something else entirely: a gene from a different species, encoding foreign material. I am not aware of any precedent for this type of intervention.

Finally, there is the intellectual issue, which I consider by far the most significant. For many neuropsychiatric disorders, we simply do not understand the normal neurobiological processes and what goes wrong with them well enough to design rational corrective measures. Thus, we are likely going to see optogenetic applications in areas in which the underlying neurobiology is relatively clear, such as visual restoration.

GEN: Last year, you received the Heinrich Wieland Prize of the Boehringer Ingelheim Foundation, an international award that honors outstanding research on biologically active molecules and systems in the fields of chemistry, biochemistry, and physiology, and their clinical importance. Your optogenetics method was described as a “breakthrough of the decade.” In response, you said, “The speed at which it has spread and been improved upon by other researchers still sur-prises me.” What do you believe has contributed to the widespread use of optogenetics in brain research? Have new technologies and methods enhanced its capabilities, and if so, how?

Dr. Miesenböck: As Steve Jobs famously said about the people standing in line outside his Apple stores: “People don’t know what they want until you show it to them.” Most scientists are also consumers of technology. They didn’t know that they wanted or needed optogenetics, but once they saw what it could do they quickly joined the queue.

What has been surprising is the speed with which new and improved light-responsive proteins have been discovered or engineered. However, despite their practical importance, all these improvements are nevertheless variations of the same basic principle of optogenetic control that we first reported in 2002.

GEN: What is the current focus of your research, and how do you envision your work evolving in the future?

Dr. Miesenböck: Neural processes occur over a vast range of timescales, from the single millisecond of an action potential to the months or years over which the brain develops. We understand events at the extremes of this range reasonably well, but there is a window in the middle that remains quite enigmatic. This window covers timescales from a few hundred milliseconds to a few hours and contains some of the most interesting neurobiology. It is at these timescales that we orient ourselves, plan and execute our actions, communicate, and transition between sleep and waking.

We are interested in neural processes that unfold at these timescales. Optogenetics plays an important enabling role in our research, but it is not an end in itself. We would like to understand how the brain works—even if it is “just” the brain of a fly.         

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