Illuminating Diseases: What is Optogenetics?

In the early 2000s, the term “optogenetics” was first coined by Deisseroth et al. to describe the stimulation of neuronal photoreceptors during imaging. Using channelrhodopsin-2, an ion channel that depolarizes in response to light, Deisseroth’s laboratory was able to use blue light to trigger spiking (the generation of an action potential) and synaptic transmission in neural circuits at a millisecond time scale.

Light therapy is used to treat jaundice and hyperbilirubemia.

Light therapy is used to treat jaundice and hyperbilirubemia.

Using select lightwaves to alter biological activity is not a new concept. Since the 1960s, blue-light phototherapy has treated millions of infants suffering from hyperbilirubinemia, a condition in which bilirubin accumulates in the blood. In fact, phototherapies are commonly used in oncology, dermatology and cosmetics clinics. Photodynamic therapy utilizes light to activate an administered drug and cause cell death and has been around since the early 1900s.

Since Deisseroth’s light-controlled neuron firing experiments, optogenetic technologies and research have boomed. Applications in microscopy, fluorescent-tagged cells, light-sensitive reporters for biochemical functions, and high-speed optical control of electrical activity in mammalian cells have all been explored. Optogenetic control in therapeutics has been a particularly promising development, as it harnesses the versatility of light in manipulating photosensitive proteins, molecules, and cells.

Optogenetics represents a new frontier in light-activated therapies because it uses genetically-encoded photosensitive domains to affect protein function and biological pathways in vivo. In a typical experimental protocol, target cells are made photoactive by fusing native proteins or molecules with a photosensitive domain. For example, scientists recently developed a method to use light to control the pacing of mammalian hearts. By tagging channelrhodopsin-2 to one or more ventricles of rat hearts, they were able to show that different beating frequencies can be obtained in vivo upon blue-light illumination. This provides a possible clinical application in cardiac resynchronization therapy. Current treatments for arrhythmia among heart failure patients involve sending electrical impulses to both chambers of the lower heart. With the channelrhodopsin system, the beating of the two ventricles can be coordinated with blue light rather than sending electrical impulses. Thus, channelrhodopsin-2 can also be used to create an optogenetic heart pacer.

One of the reasons to use light in medicine is that it is an extension of light’s evolutionary role in biology. Plants have sophisticated machinery to convert solar energy from sunlight into chemical energy and food. The visual system of organisms, based on photosensitive proteins and transduction, helps organisms find food and survive. Jellyfish bioluminescence improve survival and reproduction. This application is a driving force in natural evolution. Furthermore, the therapeutic effects of light can be very specific and localized by controlling for absorption of specific wavelengths or colors of light by photosensitive molecules. 

Compared to small-molecule approaches like ingesting drugs, light-based therapy will be faster acting, given the speed of light compared to molecule diffusion in the human body. The treatment would also be localized as it would be possible to control where to shine light and activate photoactive molecules, as opposed to chemicals which rely on concentration-based diffusion. So, by modifying genes and proteins to be photoactivatable, scientists are leveraging cellular machineries resulting from billions of years of conserved evolution.

However, therapeutics using optogenetic fusion molecules still have significant barriers to human use as it requires introducing foreign or engineered DNA into human cells. This raises concerns regarding the immune responses resulting from transplantation of foreign genetic material and proteins into humans and genetic targeting to specific cells in the body. Therapies have been tested in mice and other model organism for conditions such as arrhythmia, depression, chronic pain and addiction. In order to translate them to human use, scientists have been looking into using the adeno-associated virus (AAV), one of the smallest known virus not associated with any symptoms or diseases. Current efforts have been to engineer the AAV to deliver DNA to target cells in gene therapy as it has been proven to be the safest method since recombinant AAV lacks any viral DNA. At MIT, Professor Feng Zhang, one of the leading forces in developing the CRISPR-Cas9 system in human cells, is exploring the properties of exosomes, intracellular delivery vesicles, to deliver engineered molecules into cells. 

While there is still much research to be done to create an generalizable way to introduce genetically-encoded molecules into human cells, it is possible. RetroSense Therapeutics proved this in 2014 when their viral-vector based optogenetic therapy for retinitis pigmentosa was approved for orphan status (orphan status refers to drugs that are defined as safe and effective treatment options for rare diseases and disorders) by the Food and Drug Administration.

Given the versatile role of light, there are many ways that light-based approaches can sense, monitor and manipulate biological processes, and many more clinical applications, either to study or treat diseases. At Stanford, Professor Deisseroth is continuing his research with optogenetics to investigate schizophrenia. Dr. Jaimie Henderson is applying this tool towards understanding and treating Parkinson's disease, and Dr. Krishna Shenoy is examining paralysis and traumatic head injuries. Thus, due to the high temporal and spatial resolution of optogenetic tools, this field serves as a promising avenue towards developing therapeutics and will surely continue advancing in the future. 

Further Reading:

Kushibiki, Toshihiro, and Miya Ishihara. “Application of Optogenetics in Gene Therapy.” Current Gene Therapy, vol. 18, no. 1, 2018, pp. 40–44., doi:10.2174/1566523218666180302163814.

Naso, Michael F., et al. “Adeno-Associated Virus (AAV) as a Vector for Gene Therapy.” BioDrugs, vol. 31, no. 4, 1 July 2017, pp. 317–334., doi:10.1007/s40259-017-0234-5.

Nussinovitch, Udi, and Lior Gepstein. “Optogenetics for in Vivo Cardiac Pacing and Resynchronization Therapies.” Nature Biotechnology, vol. 33, no. 7, 2015, pp. 750–754., doi:10.1038/nbt.3268.

Williams, Shawna. “Optogenetic Therapies Move Closer to Clinical Use.” The Scientist Magazine, The Scientist Magazine, 16 Nov. 2017,

Yun, Seok Hyun, and Sheldon J. J. Kwok. “Light in Diagnosis, Therapy and Surgery.” Nature Biomedical Engineering, vol. 1, no. 1, 10 Jan. 2017, p. 0008., doi:10.1038/s41551-016-0008.