Genetics is no doubt one of the most rapidly developing biomedical fields in our century. Having added a little physics to it, the field evolved into a powerful technique called “optogenetics”, enabling researchers to command cells remotely by just putting lights on them. Initially, it has become very useful for brain researchers, and it is now helping a wide variety of scientists from different fields to decipher complex processes and networks in tissues and cells as well as offering therapeutic approaches for some chronic diseases.
The field of genetics has been evolving so fast. As we started to understand more of it, the inevitable question arose whether we can edit the genetic code (the blueprint of biological life). The answer was of course “Yes!”. Indeed, the advent of advanced gene editing methods has revolutionised biomedical research, and this year’s Nobel Prize for Chemistry has been awarded to discoverers of pioneer gene-editing technology “Crispr-Cas9”. Per definition, optogenetics is a technique that aims to monitor or control cell function using light and genetic modification. Having said that, let’s brush up our cell biology knowledge first before we delve too deeply into this fancy field.
All living cells have a cell membrane. This is not a mere coincidence as an intact membrane draws the line between life and death for a cell. In other words, the ability to keep certain molecules within the cell while excluding others is what makes the cell alive. Ions, charged atoms or molecules, are especially subjected to this highly selective compartmentalisation. Because even the slightest changes in their levels either inside or outside of the cell can cause irreversible damages to the organism. Therefore, ion transport through the cell membrane is strictly regulated by specialised gate-keepers known as “channel proteins”. With ions being charged, differences in their concentrations on opposite sides of a cellular membrane give rise to an electrical gradient, “membrane potential”, which is key to functions of many organs and systems such as nerve conduction, muscle contraction.
After this light introduction, we are ready to venture into this mysterious field of “optogenetics”. Imagine a protein that can let ions pass through the membrane only if there is light around. This particular group of photo-sensitive proteins also referred to as “opsins”, is naturally present in algae (aquatic plantlike organism). [1] Thanks to the gene modification technologies, now any cell type can express opsins after undergoing specialised laboratory steps, which led to the creation of optogenetics at the beginning of the 21st century. [2]
The concept was first introduced to the neuroscience field by brain researchers who were keen to understand which neuron groups do what in the brain. They managed to insert the gene encoding opsin into a specific type of neuron cells in the mouse. By doing so, they were able to control the neuron activity within a specific location of the brain and assess the relevant functional outcomes.[3]
In the neuroscience field, channelrhodopsin-2 (ChR2), a channel protein sensitive to blue light, is the most commonly used opsin. The blue light triggers ChR2, turning the ChR2-expressing neurons on. Pioneer scientists in the field generated a mouse carrying the ChR2 gene in neurons that were hypothesized to be responsible for thirst control. [4] Upon illuminating the brains of mice with blue light via fiberoptic technology, the activation of neurons was achieved in this particular brain region and triggered immediate excessive drinking behavior in the mouse. The results provided researchers with direct proof that thirst driving and suppressing signals drive from distinct neuron groups in the brain. This study has been followed by several other neuroscience-related optogenetics research elucidating the neuronal diversity of the brain as well as seeking answers to very fundamental questions such as “how are memories stored?”, “where does risk and reward calculation take place in the brain?”, etc. [5]
The usage of optogenetics was not limited to neuroscience, many other studies across different research disciplines have adopted this technique. For instance, it was revealed that manipulation of the cell membrane potential by optogenetic means in the pancreas could lead to insulin secretion from pancreatic cells, thus, playing important role in blood sugar control. [6] Furthermore, optogenetics has already progressed into clinical trials for diseases such as Retinitis Pigmentosa with promising outcomes, which is an incurable condition causing blindness in the elderly. [7]
Overall, optogenetics is a biotechnological tool that aims to control the cells by combining genetic and optical engineering. Although it is a relatively new method, it is becoming increasingly popular in biomedical research. In my opinion, it is only a matter of time before we see optogenetics as a treatment modality offered for chronic diseases.
Author: Yavuz F. Yazicioglu, MD
DPhil candidate in Molecular and Cellular Medicine
University of Oxford
Email: yavuz.yazicioglu@st-hughs.ox.ac.uk
References
[1] Nagel, G., Szellas, T., Huhn, W., Kateriya, S., Adeishvili, N., Berthold, P., et al. 2003. Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc. Natl. Acad. Sci. U.S.A. 100:13940–5. doi:10.1073/pnas.1936192100
[2] Boyden, E. S., Zhang, F., Bamberg, E., Nagel, G., and Deisseroth, K. 2005. Millisecond-timescale genetically targeted optical control of neural activity. Nat. Neurosci. 8:1263–8. doi:10.1038/nn1525
[3] Lim, D. H., LeDue, J., Mohajerani, M. H., Vanni, M. P., and Murphy, T. H. 2013. Optogenetic approaches for functional mouse brain mapping. Front. Neurosci. 7:54. doi:10.3389/fnins.2013.00054
[4] Oka Y, Ye M, Zuker CS. Thirst driving and suppressing signals encoded by distinct neural populations in the brain. Nature. 2015;520(7547):349-352. doi:10.1038/nature14108
[5] Deisseroth, K. 2015. Optogenetics: 10 years of microbial opsins in neuroscience. Nat. Neurosci. 18(9):1213–25. doi:10.1038/nn.4091
[6] Kushibiki T, Okawa S, Hirasawa T, Ishihara M. Optogenetic control of insulin secretion by pancreatic β-cells in vitro and in vivo. Gene Ther. 2015 Jul;22(7):553-9. doi: 10.1038/gt.2015.23. Epub 2015 Mar 26. PMID: 25809465.
[7] Henriksen BS, Marc RE, Bernstein PS. Optogenetics for retinal disorders. J Ophthalmic Vis Res. 2014;9(3):374-382. doi:10.4103/2008-322X.143379