by Aanishaa Jhaldiyal
“To raise new questions, new possibilities, to regard old problems from a new angle, requires creative imagination and marks real advance in science”.
-Dr. Albert Einstein
In the past few decades, biotechnology research has achieved some remarkable milestones. If we consider what scientists are capable of doing today, it would occur to us that many years back, this would have only been possible in sci-fi movies- making scientists a modern-day sorcerer. Breezing through a cornucopia of scientific achievements, Optogenetics stands out to be one of the most unique accomplishment made so far.
Optogenetics- how did it all begin!!
The inception of optogenetics can be traced back to the works of Oesterhelt and Stoeckenius in the early 1970s where they provided evidences that microbes express a rhodopsin-like protein (rhodopsin is a light sensitive protein that generates a biological response when light acts upon it) which can directly activate an ion channel. With time, a number of complex and sophisticated microbial systems were discovered. This was followed by successful integration and expression of these proteins in isolated cell systems, but until early 2000s no one was able to appreciate the role of such proteins in neuroscience. It was at this time when people started thinking about it, and on 11 October 2006 Dr. Karl Deisseroth was able to publish the most conclusive evidence in his article- ‘Next-Generation Optical Technologies for Illuminating Genetically Targeted Brain Circuits’(The Journal of Neuroscience 2006). He gave us an unorthodox yet trailblazing perspective to exploit these light sensitive ion channels. It was in this article where he coined the term optogenetics.
By definition, optogenetics is the amalgamation of genetics and light to control the behavior of a specific type of cell population without affecting the properties of the surrounding cells. It requires the introduction of a set of genes that expresses a light sensitive receptor protein (opsins) which can render the targeted cells- ‘light obedient’. Since its applications are limited to neuroscience, the term light obedient refers to the acquired capability of genetically engineered neurons to transmit electrical signals on exposure to light. The microbial light sensitive proteins used includes bacteriorhodopsin, channelrhodopsin and halorhodopsin (each activates the entry of different ions into the cells on encounter with light). Furthermore, Optogenetics not only encompasses the technology for expressing these microbial genes in neurons, but also includes developing conduits to deliver light to activate such systems and later be capable to map biologically faithful outputs from them.
What makes this field more interesting is its potential to extrapolate its application to freely wandering living organisms/live tissues, and not just limited to a slick arrangement of cells growing on a petri-dish! This means that any desired output could be achieved from an optically controlled cell present in an intact organism at a pre-decided period of time, making optogenetics a dream come true for the whole scientific community!
Neuroscience→ Optogenetics→ Neuroscience: a need that instigated a new field
It is an undisputable fact that neuroscience as a field has come a long way- from understanding the mechanics of action potential in a neuron to generating them from patient derived cells (using stem cell technology). However this is not enough to completely comprehend what causes/constitutes a given neuro-pathological state. In our pursuit to unravel this conundrum, we have often been stymied by our incapability to view the desired subject of our study (affected) against the whole neurological landscape (unaffected). Doubtlessly, the dream to achieve this level of precision led to the serendipity of optogenetics. The genesis of optogenetics has already been previously discussed. Now let’s look at the aftermath of its emergence.
In the last ten years of its existence, optogenetics has frankly been only able to, as Karl Deisseroth described, bring a ‘speculation into reality’. It is undergoing a speedy process of standardization where month by month improved methods are reported to optically control a neuron to transduce/silence a neuro-transmission (the image by Häusser et al. 2014 perfectly explains how optogenetics fundamentally work). Efforts are being made in all directions- from initiating studies in mammalian brain tissue samples to replicating its application in model organisms like nematodes (Caenorhabditis elegans), zebrafish (Danio rerio), non-human primates, fruit flies (Drosophila melanogaster), mice (Mus musculus), etc.
A classic example (which proves the rapid progression of this field) can be given by Inagaki et al. in 2014, who successfully studied courtship behavior in male fruit flies using red activatable channelrhodopsin (ReaChR; proteins activated by red light). ReaChR helped them to precisely control and map different sections of brain (of a free moving fruit fly). This helped them to precisely chart the neurological changes that affect the social life of a male fruit fly.
Additionally, optogenetics has been conducive in challenging previously established hypotheses. In a recent article by Do-monte et al. (2015), he used this technology (to activate/inhibit an electrical signal through a neuron) to question the role of a part of the brain (infralimbic sector of the medial prefrontal cortex) that was implicated to cause extinction of memory against an aversive stimulus.
There are numerous examples that can illustrate the importance of optogenetics to the neuroscientific community. On analyzing the celerity by which this field is burgeoning, it is expected to deliver astounding results very soon. Nevertheless, it is only time that will divulge if optogenetics can actually become our ultimate weapon towards understanding neurological disorders!!
Deisseroth et al. 2006. Next-Generation Optical Technologies for Illuminating Genetically Targeted Brain Circuits. The Journal of Neuroscience; 26(41):10380 –10386.
Deisseroth at al. Optogenetics: 10 years of microbial opsins in neuroscience. Nature Neuroscience;18(9).
Häusser et al. 2014. Optogenetics: the age of light. Nature Methods; 11, 1012–1014. Doi:10.1038/nmeth.3111.
Inagaki et al. 2014. Optogenetic control of Drosophila using a red-shifted channelrhodopsin reveals experience-dependent influences on courtship. Nature methods,11(3).
Monte et al. 2015. Revisiting the Role of Infralimbic Cortex in Fear Extinction with Optogenetics. The Journal of Neuroscience; 35(8):3607–3615.