Optogenetics: A Novel Technology With Questions Old and New

This claim about a Nobel Prize some eight years away may seem obscure, especially about a new technology that is not yet fully nor widely understood. What is optogenetics? And if it appears so groundbreaking, why do we have to wait until 2020 for its award?

Optogenetics is a novel technology that has produced some startling results in animals and thus raises questions about its future applications: Is it safe even on the animal models it uses? Could optogenetics offer better treatment than the many already existing ones? If so, does it pose similar or different questions as an invention into the human mind?

Stanford Medical School Professor Karl Deisseroth et al., have described optogenetics as a technology which "combines genetic targeting of specific neurons or proteins with optical technology for imaging or control of the targets within intact, living neural circuits."

Simply put, optogenetics is a combination of genetics and optics to manipulate single neurons using pulses of light delivered to the brain via fiber optic threads.

The ability to use light to control neurons was first theorized by the late English biologist and co-discoverer of DNA, Francis Crick, but not until the use of microbial opsins, light-sensitive proteins found in algae, could researchers study the effects of light manipulation of single neurons. Channelrhodopsins respond to blue light and activate, or "turn on" the neuron. Halorhodopsins, as well as several other opsins, respond to yellow light and inhibit, or "turn off" the neuron. These are delivered to the brain through genetically modified viruses, in a technique similar to gene therapy.

The novelty of optogenetics lies in the ability to control single neurons in living, moving animals in milliseconds and reverse the intervention just as quickly. In Deisseroth's words: "What excites neuroscientists about optogenetics is control over defined events within defined cell types at defined times--a level of precision that is most likely crucial to biological understanding even beyond neuroscience."

Optogenetics has also transformed understanding of the brain. Deisseroth maintains that prevailing use of drug therapy has many limitations: "Right now, we're treating the brain like neurotransmitter soup. That's a very limiting view and it's why drugs fail in many cases. They don't speak the language of the brain."

Attempts to reconceive the brain in terms of its electrical circuitry have yielded some successes with deep brain stimulation (DBS) with Parkinson's patients, yet the procedure requires an invasive probe in the brain, which affects many unrelated surrounding neurons. It is possible however, that with the help of optogenetics DBS, might be able to target more specific cells in the basal ganglia related to Parkinson's disease.

Successfully used in animal models, such as mice and rats, optogenetic techniques are now being used in primates as well. Researchers suggest that some of the possible applications for this new technology in humans may in treating be Parkinson's disease, addiction, aggression, schizophrenia, autism and depression. But human testing remains still distant. Perhaps this is why 2020 appears a not unreasonable estimate for any major achievement award. After all, there are many questions to be answered before optogenetics can be applied in humans.

In Deisseroth's presentation of optogenetic technology, he shows a mouse in a box wearing the blue light fiber optic sensor. The mouse is sitting tranquilly until Deisseroth flips on the light, which has been connected to the part of the brain that controls movement to the left. The mouse suddenly begins to scurry to the left in circles and continues to do so until Deisseroth flips off the light.

"So this is a little scary, right?" He allows. The audience can be heard chuckling in agreement. At the end of his presentation, Deisseroth mentions that the public needs to consider to the myriad of social, political and ethical questions raised by this technology.

Many people continue to pose questions about the safety of the lentivirus, which delivers the opsin information into the DNA of a neuron. Although these virus vectors have been "hollowed out" by removing the functional viral particles so that the virus is no longer infectious, handling requires extreme caution and is heavily regulated. As of yet, there are no such gene therapy products that have been approved by the FDA.

Ethical questions also arise:

What becomes of the individual, whose brain can now be manipulated via remote control? A mouse can be switched on and off; will humans allow themselves to be controlled in this fashion as well? Will this new technology further threaten human autonomy? After all, there are already many non-medical assaults on this autonomy through everyday experiences and institutions in modern life.

One observer asked: "Might optogeneticically modulated individuals be "hacked" -- enabling third parties to gain control over their decisions and actions?

The questions are old, but the methods are new and developing. How can humans deploy our science and medicines and retain our autonomy, even as embattled as it may be?

Dr. Lauren Milner, PhD., and Dr. Megan Allyse, PhD., post-doctoral fellows at Stanford University Medical School's Center for Integration of Research on Genetics and Ethics (CIRGE) are currently researching these questions related to optogenetics. Milner argues that for the immediate future "optogenetics is really thought of more as a research tool than an therapeutic tool," and the safety questions remain more whether the technology will work at all, rather than any potential infection or rejection from the gene therapy involved. Referring to the foreign plant DNA of the opsins, Milner comments:

Most of the research I've seen confirmed that there was very little (if any) cellular damage in the preclinical models used, and few behavioral side effects. However, it is important to remember that animals are not people, and so there will always be some risks associated with the introduction of nonhuman DNA into humans that cannot be predicted in the lab ... So while there could be unintended side effects of using this technology in people, one of the most significant risks is that it simply won't work, which could be a huge drain on resources.

Allyse also confirms that optogenetics poses few new ethical questions and remains for now largely a research tool. She cautions against viewing optogenetics as a panacea or "silver bullet" therapy : "While optogenetics research can provide fascinating insight into the mechanisms of neural action, psychiatric conditions are extremely complex and treating them requires a combination of medical, psychological and social inputs."

For now anyway, only preliminary questions can be raised about safeguards for both the subjects and the researchers. Regarding future ethical concerns, public participation at all levels of this intervention is key.