Mind control for a good cause

Almost one year ago, I wrote a post on optogenetics, a new field that combines optical techniques (playing with light) and genetic techniques (playing with DNA) to study the brain. Optogenetics is an extremely powerful technique that can be used to control the activity of brain cells. So far, it’s been mostly researched as an experimental tool, but a recent study published in the journal Nature hints at the possibility of using this technique to learn how to treat the most common neurodegenerative disorder after Alzheimer’s disease: Parkinson’s.

Parkinson’s disease, a movement disorder, affects a part of the brain called the basal ganglia, which is critical for planning movement and selecting appropriate actions. The basal ganglia can be roughly divided into two pathways (or networks of brain cells): a “direct” pathway that facilitates (or enables) movement and an “indirect” pathway that inhibits (or prevents) movement. When someone has Parkinson’s disease, it is thought that their direct pathway is not active enough and that their indirect pathway is too active, and this leads to the muscle rigidity, tremors and slowing of physical movement.

In this study, the researchers used a virus to deliver a special channel to the brain cells of either the direct or the indirect pathway of the basal ganglia in mice. This may sound confusing at first, but it’s a really clever experiment. Here is how it works: when certain types of viruses infect cells, they incorporate their DNA into the DNA of the “host” cell, such that the host starts making virus DNA, and ultimately turns into a virus-making factory. The researchers essentially hijacked this process: they engineered a virus that contained the DNA for the special channel, and therefore, once the brain cells got infected, they started making the special channel. What’s so special about this channel? It is activated by light (hence the “opto” in “optogenetics”). When blue light hits this channel, it activates the brain cells.

To tease out the differences between the direct and the indirect pathways, the researchers divided their mice into three groups: a control group (no brain cells infected with the virus), a “direct” group (the virus targets the direct pathway, such that only cells in the direct pathway have the special channel), and an “indirect” group (the virus targets the indirect pathway, such that only cells in the indirect pathway have the special channel). By exploiting this technique, the researchers were able to activate either the direct pathway or the indirect pathway of the basal ganglia simply by shining blue light onto the brain of the mice.

(I realize this is all very complicated, but if you’re still with me at this point, congratulations on completing Optogenetics 101!)

And now for the results… *drumroll* As expected, when the direct pathway was activated, the mice moved more (they ran around more, stood up on their hind legs more, etc.). And when the indirect pathway was activated, the mice froze, and overall moved less. How’s this for mind control?

At this point, it’s easy to get carried away and imagine a plethora of crazy scenarios should this technology fall in the hands of the bad guys (“And now, you will dance for me! Gnahahaha!”) However, the researchers had good intentions. They went on to activate the direct pathway in a mouse model of Parkinson’s disease, and found that this procedure rescued the locomotion deficits of the mice. And that is a wicked finding.

Unfortunately, treating humans with optogenetics is not going to happen anytime soon. There are significant hurdles to overcome before we can even think about it: working with viruses in the brain, delivering the channels only where we want them, assessing unwanted effects, and so on. That said, this study elegantly confirms that somehow activating the basal ganglia’s direct pathway could be an important therapeutic target to treat Parkinson’s disease.

Reference: Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Kravitz AV et al. Nature, 466(7306):622-6 (2010).

A new kind of mind control

Remember subliminal messages? Those images supposedly flashing too quick for your mind to register, but still managing to convince you to drink more soft drinks, eat more fries, buy a luxury car? While those days may not be over yet, new forms of mind control (albeit more biological than psychological) are emerging thanks to the tiniest of creatures, the bacteria.

A friend of mine, Cal, recently alerted me to an interesting article about optogenetics. If you’re not familiar with the word, that’s because it’s very new, and it essentially means playing with light and genetics at the same time. It’s all the rage in neuroscience right now and articles such as the one I’ll be describing in this post are popping up every week.

It all starts with a tiny little pump called halorhodopsin found in bacteria. This pump sits at the surface of cells and pumps chloride ions from outside the cell to the inside (table salt is sodium chloride - same chloride). Cells use chloride for different reasons, but this pump can be especially relevant for brain cells (called neurons). Neurons pass information to one another through electric currents. And it just so happens that chloride ions are charged negatively. That means that if many chloride ions accumulate inside a neuron, the cell becomes increasingly charged negatively, making it harder to reach the positive threshold it needs to pass currents to other neurons.

Other types of chloride pumps already exist in your brain cells, but almost nobody makes a fuss about those. So how is halorhodopsin different? This is where the “opto” from “optogenetics” comes in. This particular pump is activated by light. This means that if neurons have this special pump, you can control whether they are active or not just by flashing a light onto them.

In a recent paper published in PNAS, the researchers genetically engineered zebrafish so that their brain cells expressed the special light-activated chloride pump. The researchers then recorded the electrical signals generated by the brain cells (they look like spikes, much like what you would see on an EEG). I don’t know if you can imagine what kind of feat that represents, but I’d like to make a motion to modernize the saying “like finding a needle in a haystack” to “like poking an electrode into a brain cell of a live fish”. Once they knew what the signals looked like in normal conditions, they shone the light on the fish*, and amazingly, all the brain cells went quiet. It worked! The light activated the pump, negatively charged chloride ions accumulated in the cells and made it too difficult to reach the spiking threshold.

The black lines are the current spikes that normally occur when brain cells transmit information. The yellow section is when the researchers shone the light: no more spikes.

Now a fish doesn’t have that many brain cells to start with, and since it spends most of its life moving it’s pretty safe to assume that a large portion of the fish’s brainpower is devoted to swimming. The researchers thought they had a pretty cool tool to test this, and so they did. They put a bunch of genetically-engineered zebrafish in a dish, watched them swim around for a bit, and then shone a light on them*. Sure enough, the fish stopped moving and lost coordination. I realize we’re talking about lousy, bottom-of-the-food-chain fish here, but think about it: *that’s* mind control.

The article continues to great lengths, going into details about what specific part of the brain controls the swimming behavior and describing control experiments that confirm that this isn’t a fluke (i.e. the fish aren’t just spooked by the light). All things considered, it’s a very elegant example of how to use optogenetics to better understand the brain. And the relevance of these advances lies in the increased understanding of not only the brain but also diseases of the brain. Recently, these new techniques used in animal research gave us important insights into Parkinson’s disease.

What about using these tools as ways not only to understand disease, but also to treat them? What if we made our own brain cells express this special pump so we could use light to activate or inhibit different areas of our brains? While this may seem like science fiction right now, don’t be so sure. I attended a talk on optogenetics recently, and the researcher firmly believed that this emerging field of neuroscience would eventually cure blindness. In the meantime, let’s see if you can think of all the ethical questions this would raise…

* For these experiments, the researchers used fish in the larvae stage. The skin of the fish at that point is transparent, and this allows the light to reach the brain cells.

This little zebrafish is doing his best to contribute to science.

Reference: Optical control of zebrafish behavior with halorhodopsin. (2009) Arrenberg, A.B., Del Bene, F., Baier, H. Proc Natl Acad Sci USA, 106(42):17968-73.