Robert Gereau, PhD, is Director of the Washington University Pain Center and the Dr. Seymour and Rose T. Brown Professor of Anesthesiology at Washington University in Saint Louis, Missouri. Gereau, a leader in the field of pain research, was among the first researchers to use a revolutionary new technology called optogenetics to investigate pain. He recently pioneered new devices that will open the door for many more researchers to use optogenetics to study pain in rodents and to explore its potential to treat pain in people. Freelance journalist Stephani Sutherland recently spoke with Gereau about why optogenetics is so groundbreaking, the challenges it presents, and its potential as a pain therapy. Below is an edited transcript of their conversation.
What is optogenetics, and how does it work?
The term optogenetics comes from “opto” meaning light, and “genetics” meaning genetic manipulation. It’s a technique giving us the ability to control the activity of neurons with light, using a genetic trick to make neurons light sensitive. To do that, we take a light-sensitive protein, called an opsin, that responds very quickly to light and insert it into particular sets of neurons in the brain, using genetic manipulation. Then, we flash a light onto those cells. Because we can control the timing of the light turning on and off, we get very precise control of a specific set of cells at the exact time we want.
There are different types of opsins. Some of them, when exposed to light, activate neurons, and some inhibit them. Depending on the opsin used and the wavelength of light, researchers can ask what happens when they turn on the light and cause a neuron to fire. Or, they can use a different opsin that will be inhibitory, so when they turn on the light, that can turn off the firing of a neuron. That allows us, finally, to ask questions about how circuits in the nervous system are put together and how those circuits control different complex neurological behaviors.
This technology has created an entirely new field since 2005, when Karl Deisseroth at Stanford University published the first optogenetics paper. It’s a very exciting time because there is a lot of innovation and many exciting developments in this area, and we’re just starting to see the fruits of this work. It’s not just a flash in the pan; it’s a game-changing technology because it allows us to do experiments that were just not possible before. There are a lot of people doing really exciting things in neuroscience right now, addressing questions that have been lingering for years and years because the tools weren’t available yet.
What was the impetus to develop optogenetics?
The brain is made up of different parts—called nuclei—and the goal is to understand how they talk to each other and control complex behaviors. The driving force behind the development of optogenetics was that, for many years, we have been trying to study populations of neurons in the brain by stimulating parts of the brain and looking at changes in behavior or how different circuits are connected. You can do that using chemical or electrical stimulation, but these approaches are largely unsatisfying because they activate many different kinds of neurons, and it’s difficult to control where and when the neurons are activated.
Who came up with the idea for optogenetics?
The concept of controlling different types of neurons in the brain with light was first articulated by Francis Crick [co-discoverer of the DNA double helix] in the late 1990s. There have been a bunch of groups working on this, and they each had different approaches. Some of the earlier approaches were complicated because you needed to insert certain receptors [molecules that receive signals from outside the cell] into neurons and then inject chemicals that were light sensitive to activate the receptor.
The game changer for optogenetics came with the ability to genetically deliver a single light-sensitive component—a kind of light-sensitive machine, if you will—and that was done with the opsins. The work done in Deisseroth’s lab used what they called channelrhodopsin, which came from a single-celled algae that normally responds to light. They isolated this opsin, and when they put it into neurons, that made the cells sensitive to light. Suddenly you could control the cells’ firing by pulsing light at different frequencies. It was really a phenomenal demonstration and relatively simple. Scientists could now control specific populations of neurons using light—including cells in a laboratory dish, in a slice of brain tissue, and even in a living organism, where light activation could elicit specific behaviors that could then be attributed to a very small subset of neurons at a specific time.
Where else do opsins come from?
We have opsins in our retina that allow us to see the outside world. But neurons in the brain are not intrinsically light sensitive; they don’t have opsins, so if you pulse a light onto neurons in the brain, they don’t respond like neurons of the retina do. Today, there are a number of different opsins that researchers use for optogenetics. Since channelrhodopsin came along, light-sensitive proteins have been isolated from a whole host of different organisms. People are manipulating these opsins and trying to find out which ones have the best properties for different types of experiments.
Is optogenetics only a research tool, or does it also have therapeutic potential to treat disease?
The promise of optogenetics is in the eye of the beholder. If, for years, you’ve been trying to figure out a way to manipulate a certain type of neuron in worms and understand how that controls feeding behavior, you can do that using optogenetics in a way that you weren’t able to do before—and that scales up from tiny organisms like worms all the way to mice. You can get very specific in your questions about what types of cells regulate certain types of behaviors. As a basic scientist, that’s a very exciting tool to make progress in understanding cells, circuits and complex behaviors.
Our goal here at the Washington University Pain Center is to relieve suffering from pain. When I see a technique come along that allows us to turn off neurons with light, it becomes a very exciting prospect to develop this technology in a way that might make it possible, someday, to control pain in people.
In the case of pain, you can determine very quickly, by injecting a local anesthetic like lidocaine into a specific nerve, whether you can block someone’s chronic, pathological pain. Lidocaine injection is not a long-term solution, but if you could make the same neurons that lidocaine affects sensitive to light, and then use an implantable light source to decrease the activity of those neurons, suddenly you have a very specific and seemingly innocuous way to treat the patient. And, at least from a conceptual standpoint, this could have very few side effects. We don’t yet know what happens if you put opsins into neurons long term; that’s ongoing work. But the possibilities are quite vast for how optogenetics could be applied both to basic science, and for those of us who are working on clinical problems, to clinical conditions that cause suffering to tens of millions of people. It’s a very exciting prospect.
How is optogenetics being used to study pain in animals?
It’s very early in terms of published work that has used optogenetics to manipulate peripheral [originating outside of the brain and spinal cord], spinal cord, or brain circuits that are involved in pain. But 2016 will be a big year for this. Many pain research studies look at the activity of peripheral neurons and spinal cord neurons.
The traditional approach for optogenetics is to implant a fiber-optic cable coupled to a laser in order to deliver light to neurons in the brain. The problem is that you have to anchor the fiber-optic implant to a bony structure like the skull, which is very problematic when you try to do experiments in areas like the spinal cord or peripheral nerves—areas that are highly mobile, compared to other structures that don’t move as much.
For studies in peripheral neurons, light has mostly been delivered from the outside. You can either light the floor under the animal and look for a response, or you can sneak up on the animal with the fiber-optic laser and shine it onto the paw or ear and and see whether that modifies pain-like behaviors. Those methods are a little unsatisfying because it’s very intrusive; you’re very much affecting the behavior of the animals by interacting with them.
Having said that, we have seen some very interesting things in terms of the different types of neurons involved in pain. But we didn’t have the ability to control the activity of neurons in an animal that’s freely moving and unencumbered by cables—that’s been a real hurdle, and one of the things that certainly kept us and probably other researchers from entering the field of optogenetics in pain research with much gusto. Now there are some innovative approaches to manipulate spinal circuits in animals with implantable light-emitting diodes (LEDs)—an electronically activated light source. That changes what you can imagine is possible in manipulating those circuits.
Your lab has developed new devices for pain research in animals. How do they work?
As I mentioned, the main way that people have delivered light in optogenetic research in animals has been to use a fiber-optic laser, and a cable, to deliver light from the laser through the cable into the brain. The other approach is to use tiny LEDs that can be implanted either above or into the nervous system. Those require a power source, many of which require cables, so that also tethers the animal. Another approach has been wireless powering, which has required rather large headsets to provide or capture the power for the LEDs, but that still has the same problem—there is a giant device attached to the head. And that doesn’t really help us when we want to stimulate peripheral nerves going into the spinal cord.
My lab, in collaboration with Michael Bruchas here at Washington University and John Rogers at the University of Illinois at Urbana-Champaign, and separately Ada Poon’s group at Stanford, have been working on approaches to develop ultra-miniaturized, wireless, energy-harvesting antennas, which can power an attached LED. These devices can be fully implanted under the skin in the animal, in a way that doesn’t require anchoring the implant to the skull.
In our case, we use a flexible and stretchable antenna to capture energy from a remote power source. The antenna can be implanted in parts of the body that are subject to a large degree of relative motion, like the spinal cord or the hind limb. You can’t put a rigid device next to a nerve, because as the animal moves around, the device will cause damage to that nerve. In our case, the idea was to develop devices that have a consistency, stretchiness, flexibility and softness that matches that of the natural tissue. It can move with the body and not cause damage but still provide the LED with power.
What are the challenges for using optogenetics in animal research, and in humans?
For humans, the biggest hurdle is how to get the light-sensitive proteins into the cells you want to control using genetic techniques. Another hurdle is to choose the right light-sensitive protein for the clinical condition that you’re interested in. In the case of inhibiting pain, we want to pulse a light that will inhibit the firing of pain-sensing neurons in a sustained way, and do that in a way that is not damaging to the neurons themselves.
The device challenges for animal studies are actually greater than the ones for humans. This is because the degree of miniaturization you need is much more dramatic for this to work in a mouse than in a person. In a way, many of the hurdles associated with using electrical stimulation for pain have already been surpassed. We use electrodes in people now to treat pain; these are implantable electrodes that are positioned over the spinal cord or over peripheral nerves. With optogenetics, it’s a matter of delivering a different stimulus—light instead of an electrical field—through a device. We are working very hard to develop this technology and make sure it has no negative consequences when we implant the devices into animals.
The development of the technology side is going much more quickly than the development of the genetic techniques needed to get light-sensitive proteins into neurons safely and effectively; experts are working very hard on that too. There are exciting times ahead for those of us working on medical device development to partner with those working on the genetic techniques, to get all the pieces in place for optogenetic therapies.
It is possible that pain might be among the first conditions to be tested with optogenetics, because the affected neurons are more accessible, and so delivering light will be less invasive; it won’t require brain surgery. But there are certainly cases where you can imagine that manipulating brain circuits might also be very useful for treating pain—I wouldn’t count that out at all. But peripheral or spinal nerves might present the greatest opportunity with the least risk as an entry into using this technology to treat pain.
Do you have a prediction for when optogenetic therapy for pain might be available?
I really don’t. So much depends on the teams that are developing the genetic techniques to get the opsins into neurons and all the necessary and important clinical trials that must demonstrate safety in humans. Clinical trials of optogenetic approaches might happen more quickly in compassionate care cases—where there is intractable pain or end-of-life pain. But it’s hard to predict. Certainly it will be several years, at least, because I’m not aware of anything that’s in clinical trials so far. But I am incredibly optimistic that optogenetics will someday be used as a therapeutic treatment for pain.