The History of Optogenetics and its Potential Impact on the Practice of Psychiatry

          Neurological and psychiatric disorders have been prevalent all throughout human history, but never more poignant in this present day and age of fast paced civilization and globalism. People with these conditions not only have to endure the ordeal of the physical and psychological manifestations of these various debilitating disorders, but also have to deal with the indirect impact on their familial and workplace relationships along with consequences with regard to their socioeconomic status. In many countries around the world and especially pronounced in developed nations, mental illnesses leave a trail of suffering and disability that have significant implications on measures of wellness, productivity, and economics. Some of these disorders include major depressive disorder, anxiety disorders like obsessive-compulsive disorder and post-traumatic stress disorder, as well as schizophrenia and addictions.

          Optogenetics is described as one of the great breakthroughs in the field of neuroscience in recent history. The promise that it holds in treating a variety of medical conditions, especially neurological and psychiatric disorders brings hope to an area of medicine that still has difficulty in effectively treating many of the afflicted as well as a better understanding of the brain and how it works. This is crucial because of the way that the field of psychiatry has viewed mental illness which is limited by gaps in knowledge of how the brain works. Optogenetics is a unique approach that utilizes existing techniques and technology in a new way of conducting experiments involving live tissue in living organisms, in particular animals such as lab mice. This new approach or technique was the product of long years of hard work and dedication by Karl Deisseroth, a psychiatrist and neuroscientist at Stanford University, building on earlier work and theories put forth by Luigi Galvani, an Italian physician from the late 1700’s, who first observed that static electricity can cause movement in the leg of a dead frog; Walter R. Hess who in the 1920’s demonstrated that behavior and emotion came from electrical impulses in the brain by stimulating cat brains via implanted wires; and Jose Manuel Rodriguez Delgado, a Spanish physiologist from Yale who in the 1950’s used a device called a stimoceiver to implant electrodes into subjects' brains to ultimately evoke an array of responses including motor/emotional responses. Electrodes, however are imprecise in the specificity of the neurons they target. Deisseroth was frustrated by the difficulty in explaining away a disorder like depression to a patient, which can be the result of many things going awry within the brain and is further complicated by the wide variety of ways to treat it. Compare that scenario with the relative ease that a cardiologist can explain away damaged heart tissue and it is easy to see why the field of psychiatry can be so challenging (Colapinto, 2015).

          How exactly does optogenetics work? First let's fast forward to the 1970’s with the major discovery by German biochemist Dieter Oesterhelt, who observed the very first opsin (a type of protein) in a single-celled bacterium originating from highly saline lakes in Egypt and Kenya which prompted significant research into the phenomena worldwide. Despite the high salt content of these lakes, these particular bacteria are capable of surviving and thriving in these conditions and it just so happened they were also capable of converting absorbed light into energy. One of the difficulties inherent in neuroscience before the maturation of optogenetics was trouble working with a brain that operated at the millisecond level speed while being able to target specific neurons in specific areas in the brain. Then in 2003, a new opsin was discovered in a particular kind of green algae that can be found in freshwater ponds. In an experiment conducted by inserting these new opsins into human embryonic kidney cells, it was found that the opsins render the kidney cells responsive to flashes of blue light. This opsin is now referred to as channelrhodopsin-2 (ChR2) and is capable of turning light into electricity, allowing it to match the speed at which electrical impulses work in the brain. Despite this exciting new finding, the main issue that remained was getting these opsins into neurons in the brain, which is much more complicated than getting them into kidney cells. It wasn’t until mid-2004 that Deisseroth found his answer. A graduate student of Deisseroth’s named Feng Zhang figured out a way to migrate the opsin into the cell by way of injecting it with a virus (a process called viral transfection) and proved the concept by performing this technique on a rat neuron in a petri dish and flashing blue light over it. The light generated electrical activity via action potentials which is how neurons can communicate with one another (Colapinto, 2015).

          Sometime afterward Deisseroth and his team further refined optogenetics as a technique by attaching some DNA to the opsins which when injected into the target brain regions, will only be expressed on the desired neurons. Then the Deisseroth team developed a method of reaching the deep brain tissue injected with the opsins utilizing fiber-optic wires attached to a laser diode attached to the top of the mouse head. The ultimate culmination of these endeavors was first demonstrated when Zhang stimulated the motor cortex region of a mouse with blue light causing it to run in circles and promptly stopping, followed by sniffing behavior when the light was turned off. This finding was later expounded by further discoveries such as the utilization of optogenetics by another student of Deisseroth’s (Viviana Gradinaru) establishing correlations in Parkinson’s disease and Zhang’s findings on the role of certain dopaminergic neurons that play a role in reward response and by extension drug addiction (which is similar to findings as indicated by Dr. Stephen Steidl in regards to the dopaminergic system during his presentation at Loyola University Chicago on September 5, 2017) (Steidl, 2017). Another disciple of Deisseroth’s, Edward Boyden conducted his own research at M.I.T. using an opsin (now known as halorhodopsin) that is responsive to yellow light which results in a shutting down of neural activity. All of these experiments combined to demonstrate the strong selectivity of the neuronal populations that were the foci of opsin expression and stimulation (Colapinto, 2015).

How does optogenetics compare to how clinical psychiatry is currently conducted? Optogenetics still has a long way to go before it or something along a similar vein can be applied to human beings, despite the relative similarity between optogenetic test subjects (mice) and human brains in terms of function, especially with regard to emotional responses such as fear, anxiety, and reward. One major issue is all of the unknowns regarding injecting living people with viruses and their potential long-term effects. In the practice of psychiatry, quite often the approach to treating various disorders such as major depression involves prescribing medications that affect different systems in the brain such as the antidepressant Prozac. It was presumed for a long time that the issue in many mental disorders was a chemical imbalance (Colapinto, 2015). A big issue involving the use of drugs is the potential for undesirable side effects. Many drugs are metabolized in the liver where in some cases they are inactivated by the cytochrome P-450 family of enzymes, but in others metabolism creates active metabolites that may create an even stronger effect than the drug in its original form (also known as a prodrug). If you’ve heard the adage to beware of drinking grapefruit juice when taking certain medications, then you’ll know what I’m talking about. Grapefruit juice acts as an inhibitor of the CYP3A4 enzyme which is one of the major enzymes that metabolizes drugs (also classified as substrates). For example, this induction could potentially elevate levels of prescription drugs that someone might be taking, which would generate toxicity and potential harm. Some of the popular drugs used to treat depression (anti-depressants), anxiety (anxiolytics), schizophrenia (neuroleptics/anti-psychotics), and pain (synthetic opioids) are either inducers (which can lower levels of other drugs) or inhibitors of these CYP enzymes which creates problematic situations especially when people are on multiple drugs (Le, 2016).

Optogenetics has now had a very large impact on the field of neuroscience giving scientific researchers the ability to work with the detailed networks that constitute the makeup of the brain and have uncovered new information regarding a number of its functions such as learning, memory, metabolism, hunger, sleep, reward response, motivation, and fear. As time passes, more and more researchers in the field of neuroscience are seeing that the brain and disorders that are associated with it involve complex networks of circuitry with diseases resembling a short-circuit in the vast and extensive wiring within its frame (Colapinto, 2015). It is my belief that optogenetics, if the issues regarding usage in humans can be worked out, perhaps through further refinement or optimization of the technique can play an important role in potentially solving the issue of side effects from medications (especially multiple medication regimes). Being able to target only the specific population of neurons in specific parts of the brain (including specific systems/networks/circuits) would be a big advantage over conventional trial and error prescription medications which not only may cause side effects, but may also be a waste of time and money. This may prove to be beneficial not only to the patient’s physical and psychological well-being, but also their professional and private lives. In the grand scheme of things, the work performed by Karl Deisseroth and his peers exemplifies and demonstrates the height of human ingenuity and creativity.

References

Colapinto, John. “Lighting the Brain: Karl Deisseroth and the Optogenetics Breakthrough.” The New Yorker, 18 May 2015, https://www.newyorker.com/magazine/2015/05/18/lighting-the-brain. Accessed 12 October 2017.

“Drug Metabolism.” YouTube, uploaded by Kim T, 12 September 2008. https://www.youtube.com/watch?v=2uehdqZzKEM. Accessed 17 October 2017.

“Karl Deisseroth (Stanford/HHMI): Development of Optogenetics.” YouTube, uploaded by iBioMagazine, 20 September 2016. https://www.youtube.com/watch?v=MUGky_QaaV0&t=415s. Accessed 15 October 2017.

Le, Jennifer. “Drug Metabolism.” Merck Manuals: Professional Version. April 2016, http://www.merckmanuals.com/professional/clinical-pharmacology/pharmacokinetics/drug-metabolism. Accessed 17 October 2017.

Steidl, Stephen. “Mesopontine tegmental inputs to the dopamine system contribute to appetitively motivated behaviors in rats and mice.” 5 September 2017. Loyola University Chicago, Chicago, IL. Speaker Presentation.