It may sound like the stuff of science fiction, but the ability to manipulate cells and control animal behaviour with light is a modern-day reality, and it’s revolutionising biological research.
Optogenetics comprises various tools and techniques which combine genetic engineering with optical stimulation, allowing the activity and behaviour of cells to be controlled using light (1). These innovations have their origins in neuroscience, but have since expanded to virtually every discipline in biological research, and are now being tested in clinical settings
Origins of optogenetics in neuroscience
The brain is a remarkably complex circuit, in which signals are constantly sent and received by cells called neurons. In order to explore the intricate structure of this circuitry, and understand which cells are important for the transmission of which signals, researchers have tried for many years to precisely activate and deactivate specific cells at a particular point in space and time (2). The concept of using light to trigger such a switch was first suggested by Francis Crick, Nobel Prize winner for his work on the structure of DNA. In 1999 Crick wrote “the ideal signal would be light . . . This seems rather far-fetched but it is conceivable that molecular biologists could engineer a particular cell type to respond to light in this way (3). Within a few years, this concept was a reality.
In 2005, scientists were able to use light to control mammalian neurons using a single biological tool for the first time, one year before the term optogenetics was coined (2, 4). In the study, researchers took a protein called Channelrhodopsin-2, which is found on the surface of algae, and introduced it to neurons isolated from rats (2). Channelrhodopsin-2 is a light-sensitive channel which opens in response to blue light, allowing the movement of positively charged molecules into the cell. In algae, this mechanism is coupled to movement, allowing the cell to swim towards the light source and harness energy through photosynthesis. However, on the surface of neurons, the opening of this channel transmits an electrical signal which is transformed into a biochemical signal, and allows the cell to communicate with its neighbours (Fig. 1). Thus, blue light exposure can be used to easily activate the cells. What’s more, by carefully tuning the blue light pulses used, researchers found that they could replicate the patterns of electrical impulses naturally generated by neurons, opening the possibility that light could be used to directly control signalling in the brain and understand its complexity.
Indeed, this technology was rapidly transferred from cells in a dish to laboratory animals, with optical fibres used to transmit light directly to the brains of rats or mice which were genetically modified to contain light-sensitive tools. Using the same principle of light-inducible electrical signalling, researchers have shown that they can directly control specific regions of the brain. Motor neurons can be activated to trigger whisker movements (5), and stimulating regions of the brain associated with reward recognition and learning can promote or suppress social interactions (6). Controlling behaviour with pulses of light may sound like the plot of a dystopian thriller, but researchers hope to adapt this technology to treat seizures or Parkinson’s disease by allowing rapid non-invasive control of specific neuronal activity (6).
Transferring optogenetics to diverse systems and functions
The potential applications of controlling cells with light were quickly recognised by researchers across the spectrum of biological sciences, and various optogenetic systems have now been developed in many organisms. Using the biomedical literature search tool PubMed, the term ‘optogenetics’ returns just 3 results dating from 1995-2006, and 1,495 results from 2021 alone.
This explosion in optogenetic technologies is partly down to the discovery of diverse “photoreceptor proteins”, which sense and respond to different wavelengths of light in a variety of ways. Just as the Channelrhodopsin-2 protein responds to blue light by opening its channel pore, other photoreceptors can respond to blue, red or far-red wavelengths of light by changing shape, by forming clusters, or even by binding other molecules (1). Furthermore, some photoreceptors have functions which are activated by one wavelength of light, and inactivated by another, providing a simple on/off switch. This diversity of possible inputs and outputs means that we can use these molecular light switches in a range of different biological systems to generate specific responses.
For example, the Cryptochrome 2 (CRY2) class of photoreceptors responds to blue light stimulation by clustering together (1). Since clustering is a common trigger for the activation of many proteins, this light-activated switch can be linked to different components of a cell to allow the rapid and precise control of various processes. For instance, in the common laboratory animal the fruit fly, death of cells is stimulated by clustering of a protein called Dronc. By linking the CRY2 photoreceptor to the Dronc protein, researchers at the Institut Pasteur developed an optogenetic tool, optoDronc, which allows cells in a living tissue to be selectively killed at a specific point in space and time by exposing them to blue light7 (Fig. 2). This tool was used to investigate how a tissue facing single or multiple cell death events protects itself and maintains its integrity (7).
Clinical applications of optogenetics
As well as contributing greatly to basic research, these light-responsive tools have substantial clinical potential. The success of optogenetics as a means of controlling brain activity has prompted much excitement about the prospect of new non-invasive treatments for neurological disorders. Various optogenetic strategies have been tested in rodent models of epilepsy, in which they can successfully suppress seizure activity, and may constitute an effective therapy for drug-resistant forms of the condition (8). Likewise, optogenetic stimulation of specific neurons in a mouse model of Parkinson’s disease has been shown to alleviate the mobility-reducing effects of the condition (9). While promising, clinical translation of these approaches is still underway, and questions remain to be answered regarding how the required genetic constructs can be safely delivered and stimulated in patients.
Nonetheless, the clinical use of optogenetics in humans has already shown some success. In 2021, an optogenetic treatment successfully restored some visual function to a blind patient (10). The patient suffered from Retinitis pigmentosa, an inherited progressive blinding disease, and could not visually detect objects. Following treatment with ChrimsonR, an optimised version of the Channelrhodopsin-2 protein, the patient could perceive, locate, count and touch different objects while wearing light-stimulating goggles. This is the first reported case of optogenetics being used to restore function in the context of a neurodegenerative disease.
In summary, optogenetic tools provide rapid, precise, non-invasive control of fundamental cell functions, and as such are being increasingly favoured by researchers seeking to manipulate and understand biological systems. While their clinical use is still to be fully explored, their contribution in modern research laboratories is substantial, and is likely to increase in the coming years.
1. Krueger, D. et al. Principles and applications of optogenetics in developmental biology. Development 146, (2019).
2. Boyden, E. S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity. Nature Neuroscience 2005 8:9 8, 1263–1268 (2005).
3. Crick, F. The impact of molecular biology on neuroscience. Philosophical Transactions of the Royal Society B: Biological Sciences 354, 2021 (1999).
4. Deisseroth, K. et al. Mini-Symposium: Next-Generation Optical Technologies for Illuminating Genetically Targeted Brain Circuits. The Journal of Neuroscience 26, 10380 (2006).
5. Aravanis, A. M. et al. An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology. J Neural Eng 4, S143 (2007).
6. Li, L. et al. Colocalized, bidirectional optogenetic modulations in freely behaving mice with a wireless dual-color optoelectronic probe. Nature Communications 2022 13:1 13, 1–14 (2022).
7. Valon, L. et al. Robustness of epithelial sealing is an emerging property of local ERK feedback driven by cell elimination. Dev Cell 56, 1700 (2021).
8. Wykes, R. C., Kullmann, D. M., Pavlov, I. & Magloire, V. Optogenetic approaches to treat epilepsy. J Neurosci Methods 260, 215–220 (2016).
9. Fougère, M. et al. Optogenetic stimulation of glutamatergic neurons in the cuneiform nucleus controls locomotion in a mouse model of Parkinson’s disease. Proc Natl Acad Sci U S A 118, (2021).
10. Sahel, J. A. et al. Partial recovery of visual function in a blind patient after optogenetic therapy. Nature Medicine 27 1223–1229 (2021).