How do we get from algae that respond to light to controlling the brain? Kat Arney was joined by Isabel Christie from University College London to explain the what and how of optogenetics...
Isabel - Fortunately we can use very clever genetics to take those genes from the pond life and put those into viruses. Then we can inject the viruses into the brain of a living animal such as a mouse or a rat. The cells that we’ve chosen to target using the virus will start to express that light-sensitive protein.
Kat - So I guess like in the same way when you catch a cold, the virus is delivering virus genes into you making you go all snotty and that kind of thing? You’re actually taking theses light-sensitive genes into the brain cell of the animal you’re working with?
Isabel - Absolutely. Once the cells have become infected by the virus they start to produce that viral DNA and they start to produce those proteins.
Kat - So the proteins are in these brain cells and how do you make sure that it’s just certain types of brain cells or is it any brain cells the virus infects?
Isabel - Well, that’s the really clever bit - the genetics angles, that we can choose which cells in the brain we’d like to express the light-sensitive protein. And that’s what gives this tool such great power because we can use excitatory cells or inhibitory cells in the brain and we can target specifically which cells we would like to make light-sensitive.
Kat - What’s the benefit of making a certain clump of nerve cells, a little clump in the brain? You’re making them sensitive to light by putting this molecule in them. So you shine a light on them, they go whoo - what do you do then?
Isabel - It’s all about control. As neuroscientists we want to understand the neural circuits of the brain and one of the ways we can begin to understand is to try and control them - turning them on or turning them off at will. One of the big challenges for neuroscience was this inability to control only specific brain cells at once. The more traditional techniques, using things like drugs, tend to affect many brain cells at once. So when you put a drug directly into the brain it will spread out in the brain and it will affect all the cells in the region.
The really clever thing about optogenetics is if we make only some brain cells light-sensitive, when we shine light into that part of the brain only certain cells respond. And that give us an ability to control the brain in a very specific way, so we can test the hypotheses in a way that we just couldn’t before with drugs.
Kat - So you can say okay, if these cells go on, what’s happening?
Isabel - Exactly. Some of my research is about saying if we turn these cells on, what happens in an MRI scanner? What happens in the animal’s brains? Or if you’re researching a particular disease where you thought some particular cells were responsible for causing that something to happen in the brain, you can turn those cells on and really test that hypothesis in a very direct way.
Kat - So we’ve got the genes, they’re delivered into the nerve cells, they’re making this light sensitive protein, they’re switching on, but how do you actually get light inside the brain? Last time I looked the brain was quite dark inside.
Isabel - Yeah. It’s one of the awkward aspects, I guess, of optogenetics. Some of the first experiments that were ever done were done in a petri dish with a slice of living brain tissue. It was very easy, you could deliver light through your microscope objective or via an optic fibre, but most optogenetics these days is being done in living animals. So what we might do when we’re doing the viral injections directly into the brain we will implant an optic fibre into the brain. And then, on the day of the experiment, you can come and connect an optic fibre externally to the animal’s head.
Kat - So it’s kind of like almost plugging in a remote control?
Isabel - It really is. If you look at images of optogenetics on the internet you really will see freely behaving animals with optic fibres plugged into the back of their heads. So it can look quite shocking when you see these images.
Kat - But presumably they’re okay?
Isabel - It’s quite an invasive process optogenetics. You’re injecting viruses into the brain and then you’re implanting optic fibres into the brain. But some of the great power of this research is that you can do experiments in freely behaving animals, so if people have designed very clever techniques of connecting the animal’s head to the optic fibre so they can still move around their cage and explore and do natural behaviours.
Kat - Why is this tool so powerful?
Isabel - Being able to control the brain in such a temporal specific way. You can turn cells on exactly on and off when you want to. There are so many hypotheses. I feel like almost every neuroscientists is trying to use optogenetics because it gives you a level of control that we just never had before.
Kat - It feels like a very exciting new tool. My specialism is in genetics and I’m following crispr for gene editing, and then following optogenetics for really precisely activating cells and switching on nerve cells. Does it feel like we’ve finally got this tool?
Isabel - I think it is one of the most powerful research tools that we’ve ever had in neuroscience and I think it’s already revealing so much about the brain, Just very cutting edge and very exciting times for neuroscience.
Kat - do you reckon it’s going to be a Nobel Prize winner?
Isabel - Absolutely! I think it will be probably shared by Karl Desaro and Ed Boyden and probably Gero Miesenboeck.
Kat - And, like you say, so many different ideas to be tested out there.
Isabel - I mean it’s just so wide ranging. It doesn’t have to be all inside the brain. You can also look at the peripheral nerves and you could look at other parts of the body. It’s very powerful.