10 years of neural opsins

Just in time for Nature Neuroscience’s Optogenetics 10-year anniversary retrospective, Ed Boyden has announced the first (?) time the FDA has approved optegenetics for human testing.

The set of retrospective pieces that NN published are quite interesting. For instance:

(Deisseroth) It seems unlikely that the initial experiments described here would have been fundable, as such, by typical grant programs focusing on a disease state, on a translational question, or even on solidly justified basic science…In this way, progress over the last ten years has revealed not only much about the brain, but also something about the scientific process.

(Boyden) The study, which originated in ideas and experiments generated by Karl Deisseroth and myself, collaborating with Georg Nagel and Ernst Bamberg and later with the assistance of Feng Zhang, was not immediately a smash hit. Rejected by Science, then Nature, the discovery perhaps seemed too good to be true. Could you really just express a single natural algal gene, channelrhodopsin-2 (ChR2), in neurons to make them light-activatable?

These are from the history and future of optogenetics summaries, respectively. Many people looking back on it had similar thoughts:

(Josselyn) I thought the data were interesting, but likely not replicable and definitely not generalizable. I thought optogenetics would not work reliably and, even if it did, the technique would be so complicated as to be out of reach for most neuroscience labs. My initial impression was that optogenetics would be highly parameter-sensitive and would take lots of fiddling to get any kind of effect. I was definitely in the camp that didn’t think it would have an impact on my kind of neuroscience.

Think about their perspective at the time:

So why did it take time to develop and apply methods for placing these proteins into different classes of neurons in behaving animals? As mentioned above, the development of optogenetics was a biological three-body problem in which it was hard to resolve (or, even more importantly, to motivate attempts to resolve) any one of the three challenges without first addressing the other components. For example, microbial rhodopsin photocurrents were predicted to be exceedingly small, suggesting a difficult path forward even if efficient delivery and incorporation of the all-trans retinal chromophore were possible in adult non-retinal brain tissue, and even in the event of safe and correct trafficking of these evolutionarily remote proteins to the surface membrane of complex metazoan neurons. For these weak membrane conductance regulators to work, high gene-expression and light-intensity levels would have to be attained in living nervous systems while simultaneously attaining cell-type specificity and minimizing cellular toxicity. All of this would have to be achieved even though neurons were well known to be highly vulnerable to (and often damaged or destroyed by) overexpression of membrane proteins, as well as sensitive to side effects of heat and light. Motivating dedicated effort to exploration of microbial opsin-based optical control was difficult in the face of these multiple unsolved problems, and the dimmest initial sparks of hope would turn out to mean a great deal.

And the important thing to remember:

(Soltesz) But what made the rise of optogenetics so fast? I believe it was more than just the evident usefulness of the technology itself. Indeed, in my opinion, it is to the credit of Deisseroth and Boyden that they had recognized early that by freely sharing the reagents and methods they can make optogenetics as much of a basic necessity in neurosci-ence labs as PCs, iPhones and iPads came to be in the lives of everyday citizens. This is a part of their genius that made optogenetics spread like wildfire. The open-source philosophy that they adopted stands in stark contrast to numerous other techniques where the developers tightly control all material and procedural aspects of their methodology for short-term gain, which in most, albeit not all, cases has proven to be a rather penny-wise, pound-foolish attitude in the long run.

 

Go read this Q&A with many of the pioneers of the field. Stay through to the end of the “What was your first reaction when optogenetics came onto the scene 10 years ago?” question at least.

Here is the original paper. Don’t forget that Miesenbock’s group had optogenetics work that preceded (Boyden 2005) but never quite “made it”.

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