Seven Questions with Dr Ivo Lieberam about Optogenetics

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.

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

A Optogenetics is a new, biological technique that allows you, more or less for the first time, to exactlycontrol the firing pattern of neurons you might beinterested in with light. It is based on a gene, clonedfrom an algae species (called Chlamydomonas)which is essentially a light-gated ion channel youcan express in any biological context you want – amouse cell, a human cell or fly cell. Then, when youexpose the cell that carries this transgene to lightof a certain wavelength, it will depolarize and as aresult – if it’s a neuron – fire an action potential. Justlike that, you can feed your own information intothe neural circuit. That’s what optogenetics is about.

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

A The cell level is pretty straight forward – if you want to explore electrical properties of individualneurons, you put channelrhodopsin into them, exposethem to light and see how they respond by recordingtheir activity, for example, by patch clamping - probablythe easiest experimental system. You could lookat a circuit level either in vitro or in vivo. In that caseyou’d probably have a whole population of neuronsthat would express channelrhodopsin. You recordtheir activity, probably not by patch clamping sinceyou can’t patch clamp a thousand neurons at the sametime, but you could use optical methods to see howactivity wave distributes in that circuit.

If you start signal with optogenetics, you shine lighton the spot, then you can see how that then leads to achain reaction. On systems level, well you could - andthat has been done, obviously — put channelrhodopsininto the cells of the motor cortex, shine light on a mouseor a rat that carries this transgene and elicit very specificbehavior. Basically, you can remote-control that animal.

Q 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 inrestoring motor abilities to mice with spinal cordinjury? Could you talk more about that?

A Yes, in my group we have two interests in my lab. First, we want to develop a new type of neuroprosthesis,a neuroimplant if you like, which hassome similarity I would say to a cardiac pacemaker- it would also be able to impose a contractionpattern on muscles. For our study we have chosenthe diaphragm. In contrast to cardiac pacemaker,the neuroimplant would not interfere with musclesthrough the electrodes, but through biological tissues.Essentially the idea is to have small optoelectronicdevice that would produce light flashes and could becontrolled remotely. It would communicate with thebody not through an artificial structure but it wouldhave stem cell-derived optogenetic neurons embeddedin it, which becomes sort of a body-machine interface.

The idea behind the new neuroprothesis is tohave a machine that is partially biological. Wehave a proof of principle study with Professor LindaGreensmith’s group at UCL where we implant optogeneticmotor neurons to ganglion nerve of a mouseand then control specifically the activity of musclecontraction. That wasn’t a fully implantable device,so light had to be extrinsic - we make a small incisionabove the nerve and then we have a light guideilluminating the nerve. Still, it was a proof of principlethat this brain-machine interface we are aimingfor can work.

Q It is definitely a revolutionary idea. One might say it sounds like taken out of one of the TV showslike Netflix’s Maniac where participants of thedrug study are taking pills and then the speciallight is flashed at them to activate the drug. Whichleads me to the question you might have alreadyanswered. Do you think it’s possible, or ratherhow long do you think it would take, for us tostart using those optogenetic devices in humans,perhaps in the same way we are now using DeepBrain Stimulators?

A Yes, obviously! That is precisely why we are developing these devices, certainly not to cure micebut to help cure the spinal cord injury or ALS.This is the idea. Some of the aspects of this technologyalready exist. For example with the spinalcord injury the complication pathway between thebrain and the motor neurons directly controllingthe muscle is broken and the motor neurons don’treceive any input from the motor cortex. You couldcircumvent the lesion in the spinal cord by readingintent with electrode array which would beimplanted on the motor cortex. You could be readingthe patient’s mind and that technology alreadyexists! Then, you could feed the intent circumventingthe lesioned spinal cord directly into the optogeneticdevice and, in principle, you could controlmany groups of muscles, not just one.

The reason why we aimed for breathing in thisstudy is because diaphragm has a relatively simplemechanism; it basically contracts and then passivelyre-bounces which is enough to drive breathing.Whereas if you wanted to make somebody walk,you’d probably have to control around 40 differentmuscles in a very specific sequence. I think this isalso possible at some point, but it is definitely not thepoint where you want to start.

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

A I think it is not going to go into clinical practice within the next five years. More realisticallywe could talk about the next 15-20 years. And it’snot just the modulation of motor function. It is anobvious application because you have very definedtargets, namely the muscles. But you could alsocontrol or tune other bodily functions. We have aninterest now in epilepsy and that is a new project weare collaborating on. We could devise optogeneticor maybe chemogenetic neurons and then controlthe activity to dampen the excitation in the brain,which is essentially what is driving the epilepticactivity. And we’re doing another project where weare basically building a bridge into the glial scars in spinal cord injury. All these are based on geneticallymodified stem cell derived neurons that are eitherchemogenetic or optogenetic.

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

A: We also have another interest in my lab. Thatis in fact what most of my funding goes towards. Itturned out to be quite difficult to fund these in vivoprojects because they’re quite eccentric so fundersor editors either love it or hate it. We’ve had thisexperience when we published this in vivo studywith Linda. Nature rejected it in hours and Scienceeditors loved it. So it just shows how much dependson the editors and the reviewers. Even at the samelevel it can be really unpredictable how they react.It is quite an interesting experience.

So we are also interested in in vitro modeling,this is what most of my research focuses on. We arebasically building labs on chips, so compartmentalizeddevices that carry stem cell derived neuronsand glia in one compartment and they would havemicrochannells, and in the next compartment you’dhave the target. We think that these types of devicesare the future for drug screening. A lot of the drugs are screened on cellular systems, only remotelyrelated to what target you would have in a patienteventually. If you can have a mini-circuit that is amuch better and realistic approximation to what thedrug is supposed to act on and you probably have abetter chance on getting a realistic response. That isthe new, main interest of my lab.

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

A: Yes, and these projects are less long-term and lesseccentric. They involve collaborating with physiciansor material scientists – which is a completely differentworld for me which also introduces new challengesin finding a common language. It is also interestingexperience because it forces you to work with peoplewho are far out of your comfort zone. And that dothings that are very different from what you are doing.

by Alicja Krawczun-Rygmaczewksa