Seven Questions with Ivo Lieberam: about Optogenetics

BY Alicja Krawczun-Rygmaczewska (from the 2018 archive)

For the past few years we’ve been hearing more and more about new, state-of-the-art research technique called Optogenetics. I had the pleasure of meeting Dr Ivo Lieberam who is a senior lecturer at King’s and runs his own lab at the Centre for Stem Cells & Regenerative Medicine, where he works with optogenetic techniques almost every day. We had the opportunity to discuss optogenetics itself as well as his own projects.

First, could you please sum up what optogenetics is, in one sentence, for the readers? 

Optogenetics is a new, biological technique that allows you, more or less for the first time, to exactly control the firing pattern of neurons you might be interested in with light. It is based on a gene, cloned from an algae species (called Chlamydomonas), which is essentially a light-gated ion channel you can express in any biological context you want – a mouse cell, a human cell or fly cell. Then, when you expose the cell that carries this transgene to light of a certain wavelength, it will depolarise and as a result – if it’s a neuron – fire an action potential. Just like that, you can feed your own information into the neural circuit. That’s what optogenetics is about. 

In Nature’s review of optogenetic studies, they talk about three levels of optogenetic control: cell level, circuit level, and whole brain level. Could you think of any examples for each of those levels?

The cell level is pretty straight forward – if you want to explore electrical properties of individual neurons, you put channelrhodopsin into them, expose them to light and see how they respond by recording their activity, for example, by patch clamping – probably the easiest experimental system.

You could look at a circuit level either in vitro or in vivo. In that case you’d probably have a whole population of neurons that would express channelrhodopsin. You record their activity, probably not by patch clamping since you can’t patch clamp a thousand neurons at the same time, but you could use optical methods to see how activity wave distributes in that circuit. If you start signal with optogenetics, you shine light on the spot, then you can see how that then leads to a chain reaction.

On systems level, well you could – and that has been done, obviously — put channelrhodopsin into the cells of the motor cortex, shine light on a mouse or a rat that carries this transgene and elicit very specific behavior. Basically, you can remote-control that animal.

That sounds very sci-fi even to a scientist, doesn’t it? Now, I would like to focus on your projects. If I understand correctly, you are involved in restoring motor abilities to mice with spinal cord injury? Could you talk more about that? 

First, we want to develop a new type of neuroprosthesis, a neuroimplant if you like, which has some similarity I would say to a cardiac pacemaker – it would also be able to impose a contraction pattern on muscles. For our study we have chosen the diaphragm. In contrast to cardiac pacemaker, the neuroimplant would not interfere with muscles through the electrodes, but through biological tissues. Essentially, the idea is to have small optoelectronic device that would produce light flashes and could be controlled remotely. It would communicate with the body not through an artificial structure, but it would have stem cell-derived optogenetic neurons embedded in it, which becomes sort of a body-machine interface.

The idea behind the new neuroprothesis is to have a machine that is partially biological. We have a proof of principle study with Professor Linda Greensmith’s group at UCL where we implant optogenetic motor neurons to ganglion nerve of a mouse and then control specifically the activity of muscle contraction. That wasn’t a fully implantable device, so light had to be extrinsic – we make a small incision above the nerve and then we have a light guide illuminating the nerve. Still, it was a proof of principle that this brain-machine interface we are aiming for can work.

It is definitely a revolutionary idea. One might say it sounds like taken out of one of the TV shows like Netflix’s Maniac where participants of the drug study are taking pills and then the special light is flashed at them to activate the drug. Which leads me to the question you might have already answered. Do you think it’s possible, or rather, how long do you think it would take, for us to start using those optogenetic devices in humans, perhaps in the same way we are now using Deep Brain Stimulators?

Yes, obviously! That is precisely why we are developing these devices, certainly not to cure mice but to help cure the spinal cord injury or ALS. This is the idea. Some of the aspects of this technology already exist. For example with the spinal cord injury, the complication pathway between the brain and the motor neurons directly controlling the muscle is broken and the motor neurons don’t receive any input from the motor cortex. You could circumvent the lesion in the spinal cord by reading intent with electrode array which would be implanted on the motor cortex. You could be reading the patient’s mind and that technology already exists! Then, you could feed the intent circumventing the lesioned spinal cord directly into the optogenetic device and, in principle, you could control many groups of muscles, not just one. The reason why we aimed for breathing in this study is because diaphragm has a relatively simple mechanism; it basically contracts and then passively re-bounces which is enough to drive breathing. Whereas if you wanted to make somebody walk, you’d probably have to control around 40 different muscles in a very specific sequence. I think this is also possible at some point, but it is definitely not the point where you want to start. 

How long do you think then it could take to start using this technology to help people with spinal cord injury or ALS? 

I think it is not going to go into clinical practice within the next five years. More realistically we could talk about the next 15-20 years. And it’s not just the modulation of motor function. It is an obvious application because you have very defined targets, namely the muscles. But you could also control or tune other bodily functions. We have an interest now in epilepsy and that is a new project we are collaborating on. We could devise optogenetic or maybe chemogenetic neurons and then control the activity to dampen the excitation in the brain ,which is essentially what is driving the epileptic activity. And we’re doing another project where we are basically building a bridge into the glial scars in spinal cord injury. All these are based on genetically modified stem cell derived neurons that are either chemogenetic or optogenetic.

That sounds very exciting. Makes you think about all the future research possibilities. 

We also have another interest in my lab. That is in fact what most of my funding goes towards. It turned out to be quite difficult to fund these in vivo projects because they’re quite eccentric so funders or editors either love it or hate it. We’ve had this experience when we published this in vivo study with Linda. Nature rejected it in hours and Science editors loved it. So it just shows how much depends on the editors and the reviewers. Even at the same level it can be really unpredictable how they react. It is quite an interesting experience.

So we are also interested in in vitro modelling, [and] this is what most of my research focuses on. We are basically building labs on chips, so compartmentalised devices that carry stem cell derived neurons and glia in one compartment, and in the next compartment you’d have the target. We think that these types of devices are the future for drug screening. A lot of the drugs are screened on cellular systems, only remotely related to what target you would have in a patient eventually. If you can have a mini-circuit that is a much better and realistic approximation to what the drug is supposed to act on, you probably have a better chance on getting a realistic response. That is the new, main interest of my lab.

Much more resembling a real-life type of the situations right?

Yes, and these projects are less long-term and less eccentric. They involve collaborating with physicians or material scientists – which is a completely different world for me which also introduces new challenges in finding a common language. It is also interesting experience because it forces you to work with people who are far out of your comfort zone. And that do things that are very different from what you are doing.

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