Engineered protein controls complex behavioral circuits using magnetism

Credit: Josh Brown/SciTech Editor Credit: Josh Brown/SciTech Editor

This past month in an early release to Nature, the lab of Dr. Ali Güler at University of Virginia demonstrated the ability to remotely control the activity of specific neural circuits using magnetic fields at a distance.

This discovery is the newest in a line of method research in the field of neuroscience that is rapidly approaching the concept of being able to specifically target certain cells and generate a specific behavioral or phenomenological experience; one might say “mind control.”

At first, the idea of scientists being able to control someone else’s behavior rapidly and non-invasively may seem terrifying, this new method is not that much more dystopian than the myriad of modern methods of neural mind control to which we have access today.

Let’s first take a few steps back. Only a little more than 10 years ago, the best methods available were electrical patch clamp stimulation and psychopharmacology. Electrical patch clamp stimulation targeted a specific area of the brain, but was not specified to a specific type of neuron; this means that researchers were unable to stimulate at a fine resolution. Psychopharmacological methods were able to target a specific system of neurons that all expressed the same receptors, but was not specified to an exact region of the brain. These were the methods that have been used in neuroscience for most of the 20th century and while many researchers were able to make significant advances using them, these limitations still posed significant issues.

These are the methods that have been used both in research and clinically for much of neuroscience’s history. We have a slew of medications that are designed to interact with individual receptors in the brain, but these can have drastic side effects due to their lack of location specificity. According to Carnegie Mellon Assistant Teaching Professor in the Department of Biological Sciences, Daniel J. Brasier, “the manipulations we’re talking about now [magnetogenetics] are less scary because they are only going to affect very particular targeted area of the brain; for example, antipsychotic medications for schizophrenia block dopamine. In separate parts of the brain, dopamine is necessary for movement; people can take anti-psychotic drugs and develop Parkinson-like symptoms.”

In order to address these problems of specificity in location and cell type, scientists turned to genetic modifications to provide the necessary targeting abilities. Researchers introduce a viral vector that interacts with a specific neuron type and induces the production of a Channelrhodopsin protein. This protein, when stimulated by light, causes an influx of positively charged ions, paralleling the functioning of indigenous receptors when activating the cell. Through this method, fiber optic cables can be implanted in the target regions of the brain being studied and then this specific subset of cells can be activated by turning on the light.

By this technique scientists are able to uncover what effect on behavior or “thought” the activation of this specific set of cells have in this specific region of the brain. However this method, too, has some shortcomings. First is the invasiveness of the procedure required to implant the fiber optic cable in the brain which has the potential for damaging other brain structures and resulting in infection.

Second is the time delay in activating the targeted cells; using optogenetic techniques these cells can take between 20 seconds and a minute to be activated. Brasier describes that while still an improvement over pharmacological methods, this delay poses problems for researching the activity of neural networks in the brain since much of the functioning of the network is determined by how different cells interact over a course of time rather than just by their location. Two cells might both be activated, but without precise data regarding time it is difficult to determine which cell is activating the other and how the circuit mediates the observed behavior.

The new magnetogenetic techniques pioneered by the lab of Dr. Ali Güler present a solution to these previous problems. The Magneto protein does not require any invasive surgery to be able to be activated and are able to work on the scale of a second or less, much closer to the activation capabilities of neurons themselves.

Brasier asserts that “By looking at precise temporal patterns and controlling neurons in [said patterns], we can understand how the timing, relative timing of activity in a couple of sub populations in neurons affects behavior, or memory, or perception, and so we can not only say ... inhibitory inter-neurons that express this gene, what do they do for behavior when I turn them all off/on’ now I can say what happens when I turn them off for one second, off for two seconds—introduce a pattern of activity ... get at how the timing of activity relates to behaviors and perceptions and so on.”

This means that we have an increased ability to test specific patterns more similar to neurons’ natural firing rates. In Brasier’s words: “[We are] getting much closer to the time scales that neurons actually communicate with each other; this allows the ability to have more precise control over the pattern of activity. Rather than blasting the neurons high or turning them all the way off, you can have a finer control over the finer temporal patterns these neurons are having.”

Electrical stimulation gave researchers specificity in location; pharmacological methods gave researchers specificity in cell type; optogenetic techniques blended these together for greater control; and now magentogenetics is giving scientists the ability to control all of these other factors as well as controlling the specific timing of these events.

So what do these techniques mean for our understanding of the brain or our reality? Will we soon be controlled by our magnet wielding overlords?

When asked if these if sensationalized fears that this might be the grounds for “mind-control,” Brasier responded, “Yeah, I think that would be possible in principle. Even now you could find a spot where you could implant things and make my arm twitch, and, for a couple hundred dollars, you can get a little kit where you can do a little surgery on a roach, and you can have a radio controlled roach,” Brasier said.

“Even more complicated things people have done to influence mouse behavior. In some ways, [humans are] even easier to control than mice because our brains are bigger, and the targets are bigger. Technically, I think it’s quite possible to at least control movement; we understand a fair amount about the area of the brain that move the arms around, move the legs around and so on, and also on the areas that first receive sound and visual perceptions.”

We don’t have as good a map as of yet about what comes between sensation and perception; it may be possible in the next few decades to be able to alter somebody’s, give somebody a very particular perception; there’s one paper that was published three years ago, where they found a way to [alter perception] with optogenetics.

They called it implanting a memory; they activated in a mouse the neurons which were previously active in a red room, and then give the mouse an electric shock; the mouse behaved as they were shocked in the red room; and so we can maybe put in false memories, manipulate people’s memories, and so that’s something that is very scary to think about in a lot of ways.”

“Even the experiment used to pioneer the Magneto protein provided grounds for this impressive and intimidating control over perception and thought.”

Brasier comments that “They turn on the brain’s reward center when the animal is in a green room, animals develop a strong preference to going into the green room. Already with the very first report about this protein, they’re already essentially doing a thought-implantation-like-thing where they’re impacting the way an animal feels about a specific area.”

However, within the context of previous methods before magnetogenetics, this power does not seem at all that surprising. Psychopharmacological methods have been modulating and altering perception from even before we understood the methods. Examples range from prescription anti-psychotics to your morning coffee. These all alter in different ways how we experience our reality by introducing an outside factor and inducing a change at the neural level.

Optogenetics and magenetogenetics now serve as an evolution in the precision and accuracy of these methods so that potentially these desired effects are achieved without any of the side effects that come along with the extremely complicated system that is the mammalian brain.

The dopamine system in one part of the brain helps to regulate muscle movement and in another regulates the reward and attention systems of the brain.

A malfunction in the first yields Parkinson’s Disease and in the latter yields Schizophrenia. Many of the psychopharmacological methods for treating these diseases yield side effects by activating or deactivating the other system.

Electrical implants have been devised for Parkinson’s patients to activate these specific cells in this specific area, but that method requires an invasive surgery that opens up the patient to all sorts of complications and potential damage.

Magnetogenetics seems to afford an opportunity to negate most, if not all, of these potential side-effects by being able to specifically target a distinct sub-population of neurons in a specific region of the brain without the need for invasive surgery.

This opens up not only a larger realm of study with human subjects, it also may allow for more rigorous applications in other realms.

Perhaps magnetogenetics may have implications for future treatments to deep-brain disorders. As we become increasingly able to determine the functions of circuits, we may be getting increasingly close to being able to control them.

While this discovery may be leading us down the path of “mind-control,” it is a path we began with the very inception of the field of neuroscience and this discovery is merely providing enhanced precision and safety to the methods of “mind-control” that are currently and readily being used by researchers and physicians.