Summary

Optogenetics is a biological technique that uses light to control the activity of neurons or other cells. Simply, take a protein that converts light into electrical activity and put it into neuronal targets. Then shine a light and stimulate the neurons remotely allowing for precise manipulation of brain circuits. More precisely, the technique adds light-responsive proteins called opsins, specifically channelrhodopsins**,** to the genetic code of the target cell. When activated by light, opsins cause depolarization or hyperpolarization of the cell membrane, with resulting cellular excitation or silencing on a millisecond time scale. The technique was first applied in neurons but can be applied to any cell.

Viability (2)

In 2005, Edward Boyden and Karl Deisseroth at Stanford University attempted to genetically encode brain cells that were photosensitive. They confirmed that the opsin called channelrhodopsin can be transduced into neurons to allow regulation of their electrical signaling. The UV-responsive protein Channelrhodopsin-2 has subsequently been used for the activation of in vitro neuron in mice. Optogenetics is still in its early stages in human disease models. However, recent clinical trials are working on the use of optogenetics to relieve vision loss, deafness, pain, and other conditions in humans. The first application of optogenetics in a human disease model was in 2016. Although at present there have been no human trials. We should expect Organoids to play an important role as a research tool that enables the mapping of the human brain connectome.

Drivers (4)

On the supply-side, the optogenetic toolbox is expanding with a broader range of neuronal activators and inhibitors with distinct wavelengths of excitation, ion selectivity, and kinetics. Research continues into proteins sensitive to different wavelengths to increase the brain regions that can be probed and increase light sensitivity to reduce the amount of light needed. On the optical side, laser diodes have proved to be the most cost effective laser and the broad applicability of this laser is driving down costs. On the demand-side, temporally precise, non-invasive control of neural activity is a major goal of neuroscience opening up transformative treatments in neurological disorders as well as Neuroprosthetics and Brain-Computer Interfaces. Optogenetics has the potential to stimulate any cell remotely which has gamechanging implications for the treatment of human disease and wellness.

Novelty (5)

Optogenetics is a tool to remotely manipulate cell activity. Other techniques use chemical or electromagnetic approaches to achieve the same goal with different trade-offs. In this sense, it competes with almost all drugs and techniques like Deep Brain Stimulation and Neuroprosthetics which use electromagnetism to modulation. The advantage of optogenetics is that it is possible to control the timing, location, and intensity of the signals very precisely in a way that is not possible with other techniques. Additionally, it is an inexpensive method, as it uses easier methods to generate light sources, such as the light-emitting diode (LED) or laser. Another advantage of optogenetics over pharmacological techniques is that it can precisely target the cell, which leads to much fewer off-target effects. Other less mature approaches such as sonogenetics genetically engineer cells to respond to ultrasound rather than light, in the long-term this could prove to be a compelling alternative to optogenetics.

Diffusion (3)

The big barrier to adoption was obviated in 2020 when a non-invasive approach was introduced that could activate neural circuits in the midbrain and brainstem at depths of up to 7 millimeters from a red light outside the skull. The approach also delivers a PHP virus that can be injected into the blood rather than having to inject the virus into the brain with a needle. This non-invasive approach now needs to be applied to non-human primates and then eventually humans. For broader adoption and applicability, more work is required to limit excitation or inhibition to only the target neurons, and a deeper understanding of the fact a light-evoked response may not mirror the spontaneous biological response of neurons in the absence of light.

Impact (5) High certainty

The ability to precisely and non-invasively modulate cells, even if just neurons, is almost certainly one of the most important tools humans have created. All pharmacology is an attempt to exerts some biochemical or physiological effect on a cell. Optogenetics offers the potential to precisely and remotely activate or inhibit a cell or group of cells, which with enough knowledge, allows for cheap and precise cell manipulation. A simple example would be to block pain signals for back pain. Or even repair cellular breakdown to “fix” failing organs removing the need for Xenotransplantation. Or bigger picture, target the causes of ageing at a cellular level to increase human longevity and combining with Organoids and Whole Brain Emulation research to develop functional models and simulation of the human brain.

Timing (2030+) High certainty

Optogenetics is an extremely impactful technology in the long-term but is still in its early stages in human disease models. Current clinical trials are working on the use of optogenetics to relieve vision loss, deafness, pain, and other conditions in humans. Techniques will continue to improve and we should expect the timing to be 2030+, a deep into the 2030s. The timeline is a function of the length of time to bring gene therapies to market and from the current clinical trial timelines with optogenetic cochlear implant aiming for approval in the early 2030s (See ‣).