Neurology Central

A decade of optogenetics: what have we learnt?

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The Breakthrough Prize at the end of 2015 highlighted some of the most influential breakthroughs and developments across the fundamental sciences. One of these prestigious awards was presented to Karl Deisseroth (Stanford University; CA, USA), a psychiatrist come basic neuroscientist who led research into the development of optogenetics, a form of microbial opsin engineering enabling optical control of specific nerve cells in living mammals. Since Deisseroth’s initial paper on the technique over a decade ago it has been applied and utilized in an array of different studies investigating neuronal circuits and neurological disorders. We talked to Professor Deisseroth to find out more about the history of optogenetics as well as what to expect over the next decade of development.

Did you always believe that optogenetics would have the impact it has had on the field to date?

Well there was always hope that it would be useful and that was why we were working on it, but I don’t think anyone could have predicted just how useful it has become. We did come up against a lot of problems trying to get all of the component parts of the technology working together however, it wasn’t easy.

It took about 5 years of intensive research between 2004 and 2009, incorporating a long series of different discoveries and the development of a range of new technologies. Over this period it became more and more clear that we were getting somewhere and achieving something significant. Since then we’ve seen an enormous burst of applications of the technology, providing new insights into biology. It’s been really exciting to be part of that.

What were some of the biggest challenges that you faced in those 5 years of intense development?

There were a lot of them.  If you’re inserting a gene from a microbial organism into specific neurons within a living, behaving mammal, making sure the gene is functional and that you can deliver light to the brain effectively to activate the protein encoded by the microbial gene, as well as ensuring that the process is safe and well tolerated, there’s a lot of things that can go wrong – and indeed there were a lot of problems.

Firstly, we had to work out how to get light deep into the brain, as the brain is outside the reach of visible light from the outside. Light also usually scatters within the brain, causing photons to bounce off in random directions. We therefore needed to build fibre optic and laser diode interfaces to enable us to get light into the brain in a way that is compatible with free behavior in mammals.

Following this, we then had to work out how to get the microbial opsins, which are essentially light-activated regulators of the electrical currents that flow across cell membranes, into a specific subset of cells. This was probably the biggest challenge; working out the targeting strategies to make sure that the technology was cell type-specific. We had to make a lot of foreign proteins in neurons that are very sensitive, as well as ensuring that the technique was safe and well tolerated on behavioral timescales.

That’s just a taste of the many challenges, however although it was a long process, it was a very rewarding one in the end.

What was the initial inspiration behind your work on optogenetics?

Answering the question of ‘how can we get neurons to be selectively activated?’ was something that people had wanted to do for a long time but had not known how to go about it. In fact, Francis Crick even suggested light as a method for activating neurons. The hope was already out there, it was just a matter of discovering how to get it to work.

I had my own inspiration from a couple of sources.  I’m a psychiatrist and I not only treat patients with medication but also with electrical brain stimulation therapies such as transcranial magnetic stimulation, vagus nerve stimulation and electroconvulsive therapy, but none of these are nearly as specific as we would like. They all use electricity but none of them are cell type-specific and so they are very limited in terms of how much you can do before you start causing adverse side effects.  I have carried out more than 200 electroconvulsive therapy procedures – it’s very effective and really helps patients, particularly those with severe depression, but it’s not an elegant and precise procedure. Addressing this was therefore part of my inspiration.

On the other hand I’m also a basic neuroscientist; I did my MD PhD training in synaptic physiology and electrophysiology and in some ways the same challenges of being a psychiatrist map onto basic neurosciences.  When investigating how the brain works you can’t usually turn particular cells on and off so you don’t really know what they’re doing – you can guess and make correlations but you still don’t really know. Changing that was definitely a big part of my inspiration too.

Do you think that optogenetics has a role in the clinic?

I think its biggest impact by far is in basic science and discovery for the brain and that will have an indirect, and potentially very powerful, effect on the clinic, because any type of therapy will become smarter once you really understand what the key principles of the brain function and dysfunction are. That could include everything from vagus nerve stimulation to transcranial magnetic stimulation to pharmacological treatments; even to talk therapies and all combinations thereof.

I think in many ways we’re already seeing ‘optogenetically inspired’ direct therapies being tested. In December (2015), there was a paper by Terraneo et al. discussing an optogenetically inspired treatment for cocaine addiction (Deisseroth’s News & Views article on the research is here). After evaluating research indicating that optogenetic stimulation of the prelimbic frontal cortex may inhibit cocaine seeking in animal models, the team came up with an idea for a novel and precise treatment target in humans with cocaine addiction, and it looks good in the initial studies. I definitely think the biggest clinical impact will be through knowledge-guided treatments such as this, and that’s already happening.

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