Optogenetics VS Chemogenetics
A Neuroscientific Technological Review
About 15 years ago, a revolutionary neuroscientific technique was discovered. It was made possible by a protein found in unicellular algae called channelrhodopsin, which played a key role in the plant’s ability to perform photosynthesis. When it detected sunlight, the channelrhodopsin signaled to the rest of the plant to indicate that it should absorb the sunlight and begin the photosynthetic process.
Once this was determined, scientists realized that they could utilize this in the human brain. If they edited specific neurons to express channelrhodopsin and applied light to the edited neurons, they could control the activation levels of those neurons without also unintentionally stimulating nearby groups. This was knowledge that became widely spread within the field. Only a few years later, a “younger sibling” of sorts for this technology was developed, one which unlocked new achievements in this field. However, it was far less discussed and largely fell beneath the shadow of the initial invention. While they had their similarities, each version of the technique had its own advantages and use cases. In this article we’ll dig into each technique, and then put them head to head.
- What is Optogenetics?
- What is Chemogenetics?
- Types of Chemogenetics
- How do they Compare?
- What are their Applications?
- Conclusion
- Key Takeaways
What is Optogenetics?
Optogenetics is the first version of the previously mentioned techniques. It utilizes light and genetic engineering to control neurons in the brain with the help of channelrhodopsin or a different type of opsin protein.
The naturally occurring process that opsins manipulate when performing optogenetics is that of action potentials. In every neuron, there are channel ion receptors which separate sodium and potassium ions. When activated, the receptors will open up and the two types of ions can mix. If they get mixed up, they generate an action potential and the neuron will fire. In optogenetics, opsins are injected into neurons and attach themselves to the receptors. When neurons which have been edited to express opsins have light shone on them, they will manipulate the receptors either to open up more and depolarize the ions (increases neuronal activity and is often referred to as excitation of neurons) or block the receptors from opening in times when they would naturally therefore hyperpolarizing them (decreases neuronal activity and is often called inhibition of neurons).
What makes optogenetics preferable as opposed to other methods of brain stimulation such as deep brain stimulation (DBS) or transcranial magnetic stimulation (TMS) is that only neurons which have been edited to express the opsin will have a reaction when light is shone on them, so people can target specific neurons or groups of neurons without stimulating any nearby ones unintentionally. This is very helpful both in conducting research about neuronal connections and treating brain based conditions, which are the two main buckets of optogenetic applications.
Additionally, there are many different types of opsins which have been discovered since the initial discovery of optogenetics using channelrhodopsin, and not only does each type have its own abilities but they are also all reactive to different color of light (i.e. channelrhodopsin is sensitive to blue light). Therefore, someone can have multiple types of opsins in their brain at once and use one function without it having any impact on the other(s).
Optogenetics has many incredible use cases throughout neurological conditions which we’ll get into later on. However chemogenetics does as well, so for now we’re going to zoom in on what that’s about.
What is Chemogenetics?
Chemogenetics is another neuroscientific technique used to modulate neurons, but instead of using light and genetic engineering it uses genetic engineering in a different way, and coupled with chemical drug reactions instead of light.
While optogenetics was initially discovered and inspired by the naturally occurring protein channelrhodopsin, chemogenetics was initially discovered and inspired by naturally occurring transmembrane proteins called G-protein coupled receptors (GPCRs) which are used for biological processes relating to inflammation and neurotransmission.
Instead of using light to manipulate neurons, chemogenetics uses drug based reactions between ligands and receptors (which are each specially engineered). The most popular method of this is called DREADD, which stands for designer receptors exclusively activated by designer drugs. Instead of being genetically modified to express channelrhodopsin, ion channel receptors are genetically modified to contain designer receptors. These receptors are designed to react to a certain type of designer drugs (the types vary but are always paired with a corresponding type of receptor). These drugs are often referred to as ligands, which is their biological name. Ligands are defined as any molecule that irreversibly bonds to a receptor, and they must be both inert (not reactive to other structures) and potent in the protein they are intended to deliver.
When looking to control a neuron, the ligand is released and the neurons which have been modified with designer receptors will have a reaction. However unlike optogenetics, just one activation will last up to multiple hours after it is employed.
One type of popular DREADDs are the human muscarinic (hM) DREADDs, which are reactive to CNO. The cool thing about these is that the one type of ligand (CNO) can be excitatory or inhibitory depending on if the receptors being used are hM3Dq (excitatory) or hM4Di (inhibitory). Another type are KOR (kappa opioid receptor based) DREADDs which edit neurons to express KORD receptors and are activated by Salvinorin B ligands (SalB).
KOR DREADDs are also inhibitory, but what gives them a special edge as opposed to just using hM4Di and hM3Dq receptors in this context is that you can perform multiple functions in the brain at once using these without activating other areas of the brain where chemogenetics is being performed. Since hM4Di and hM3Dq are activated by the same ligands (CNO), they can’t be used separately in the brain because deploying these drugs would activate both functions. However, using KORs in one spot and a CNO activated receptor in another enables patients to have multiple types of chemogenetic applications in their brain which won’t disrupt each other.
Now that we understand how each method works, let’s explore their similarities and differences to get closer to the big final question… which method is superior?
How do they Compare?
Right off the bat, there’s some obvious similarities: they both use genetic engineering to manipulate neurons, they both use adeno associated viruses (AAVs) for insertion and take 3 weeks to express the material they genetically modify neurons with, they both manipulate the process of action potential through the increased or decreased opening of ion channels, and both sadly are still in the mice trials phase of their development.
One semi similarity is that at least in some scenarios they each enable multiplexing (using the technique for more than one thing in the brain at a time). However, they each have their limitations in this sector because in chemogenetics you can’t have any two pair of hM DREADDs and in optogenetics you can’t have a pair of opsins activated by the same light without activating both each time.
A key difference is that while applying optic light to the brain consistently is generally not harmful or damaging, patients being treated with chemogenetics have experienced off target effects of the drugs over time and collateral projections of the DREADD activation as well.
Another big difference between the two is the incredible temporal resolution of optogenetics in contrast with the long term activation properties of chemogenetics. While someone can begin and stop performing optogenetics in their brain in just seconds with the click of a button, one chemogenetic treatment can last hours once employed with the patient having no control over its intensity or duration.
While having precise temporal control at all times can be very helpful, the longer term nature of chemogenetics is at times helpful when attempting to treat something such as an epileptic seizure which can last a long duration and requires active treatment the entire time. In that scenario, having to keep up a consistent application of light and (based on the current state of the technology) be tethered to an energy source for an extended period of time to maintain the light source is significantly less convenient.
However, epilepsy is only one of the many applications which these technologies can have. There are tons more throughout the realm of brain based disorders, and even research.
What are their Applications?
Both methods have similar applications, since they achieve the same task simply in different ways. There are two main buckets which the applications of optogenetics and chemogenetics fall under: treatment for brain based conditions, and researching synaptic connections.
The first is treatment for brain based disorders, which encompasses a variety of neurodevelopmental, neurodegenerative, and psychiatric conditions. This bucket is split between uses of the activation of neurons, and inhibition of neurons.
Excitation is useful for many neurodegenerative conditions. These are conditions such as Parkinson’s and Alzheimer’s, where neurons in a certain area degenerate in their abilities over time, leaving the patient who has the condition with lessened abilities to perform certain tasks. By performing excitation on the neurons in these areas, optogenetics or chemogenetics can force the neurons to stay active more often, which enables the patient’s neurons to either continue to work well, or improve the abilities of neurons which had been degenerating to combat the adverse effects of these conditions.
Inhibition of neurons is more commonly used for psychiatric disorders such as anxiety. In these conditions, certain groups of neurons have too much interaction with one another leading to effects such as too much worrying to a point at which it’s unhealthy. By inhibiting these neurons appropriately, scientists are able to limit the amount of neuronal activity in these areas to a standard amount, and decrease the effects of the conditions on a patient’s everyday life.
For research, excitation of neurons is used to understand neural pathways. There are billions of neurons in the brain, and they all connect to various other neurons through pathways called synapses. Based on the abundance of neurons and synapses densely packed in such a small area, scientists are still far from understanding all the synaptic connections in the human brain. The largest animal this process has been fully executed for is a fruit fly, as the standard process for doing this (which you can read more about in my connectomics article :) ) is very tedious.
However, with optogenetics/chemogenetics, we can research the synaptic connections differently. Since these techniques enable us to activate specific neurons without activating other nearby ones, the typical way to achieve this is by activating one specific neuron, and seeing how the firing of that neuron spreads to other neurons in order to determine the synaptic connections at every level. Not only is this helpful for research, but understanding these connections could also enable more precise understanding of brain based conditions, which would lead to even better treatments for them.
Both applications have the potential to have immense impact in the science and medical worlds. But using which of the techniques are the applications better executed?
Conclusion
While both techniques are very useful and have their different strengths, overall for the time being optogenetics is the winner of this comparison. Its incredible temporal resolution as well as the lack of harmful side effects and its increased level of control and popularity distinguish it from its sibling technique. I love a good underdog story as much as the next person, but based on this research it appears that optogenetics is more common for a reason.
Both techniques are still in very early stages of development, but their constant growth and progress serves as an indicator that their potential is huge. DREADDs recently utilized an anti smoking drug to control cells, and just this year optogenetics was used to help a blind man see. These unique technologies are unlike the current status quo, and so are their many applications.
Optogenetics and chemogenetics enable a truly exciting future for the fields of technology, science, and healthcare. Their journey is only just beginning, but it’s clear already that they can change the world for the better.
Key Takeaways
- Optogenetics is a neuroscientific technique which uses light and genetic engineering to control neurons in the brain.
- It does so when neurons are modified to express cells called opsins, and then light is applied to these neurons from an invasive BCI which activates the light and controls ion channels to create action potentials.
- Chemogenetics is a similar technique which uses designer ligands and receptors to create chemical drug reactions which are used to control neurons.
- The most popular technique for performing chemogenetics is DREADD: designer receptors exclusively activated by designer drugs (drugs = ligands). Neurons are modified to express special ion receptors and drugs/ligands activate them as opposed to light.
- They have a lot in common such as that they both serve the same purpose, can be excitatory or inhibitory, and are still in early stages of development. However, they also have key differences such as optogenetics’ strong temporal resolution versus chemogenetics’ consistent multi hour activation.
- They are each used for a variety of brain based disorders as well as for research about synaptic connections in the brain.
- For the time being, optogenetics is the superior method as it has better temporal resolution, is easier to control, and is safer given its lack of harmful side effects.
- Both methods have incredible potential and a variety of important future applications!
Thank you so much for reading my article, I hope you enjoyed it! My name is Raina Bornstein, I’m 15 years old, and I’m passionate about branches of neuroscience, neurological conditions, and biotechnology. I’d love to connect on LinkedIn or Twitter, or you can reach out to me at rainabornstein@gmail.com to talk or collaborate. I can’t wait to hear from you!
