Proteins as tools for research

I’m gonna talk a little bit about the new project I’m taking on (which I was going to start working on this past week, but a nasty cold set me back a bit, so I haven’t actually done anything with it yet. I’m almost fully recovered though!).

Basically this new project is testing a super cool tool, and that tool hinges on the fact that proteins can do things based on their shape. What we’re doing is shining light at proteins to make them change shape and do something we want. And because we control when the light goes on and off, we can control the precise moment that this protein starts doing its job, and the precise moment when it stops. Which is pretty useful for studying how things work and interact in a cell! Also this concept has actually been around and used for awhile, and I’m just testing the tool being used in a slightly new way. And I didn’t develop or create it, I’m just testing it in a slightly new application to see if it works in our frogs.

Okay, so why are proteins so amazing? Proteins are what actually do most things in your cells (and outside them). They do this by generating chemical environments that facilitate certain reactions, they bind molecules to recognize them or change what they’re doing, and they provide structure and support and sometimes elasticity or shape.

A quick refresher for people who don’t know/remember: proteins are made up of amino acids. Each amino acid has a certain shape and certain chemical properties (some are acidic, some are basic, some are hydrophobic, some are hydrophilic, some are big and take up a lot of space, some are tiny and can tuck into small pockets, some are very flexible, and others are very rigid and are locked at certain angles). The protein is sort of like a string of beads, where the amino acids are the beads. This string then gets arranged to form a dense ball in a certain shape, and this shape (along with the locations of the amino acids within it) determine the protein’s function. That shape can determine whether or not the protein can bind other things (imagine puzzle pieces fitting together), and how well it can bind those things.

But these shapes aren’t static. They can be changed by other proteins or molecules binding. They can also be changed by the chemical environment (because it changes how the amino acids interact with each other and their surroundings), which is influenced by electromagnetic forces such as light as well. Basically, certain wavelengths of light can change certain proteins’ shapes. And this can cause all sorts of things to happen depending on what the protein is.

For an example, this is what a tool called optogenetics does. My project isn’t optogenetics exactly (I’m working with different proteins to do a different thing in the cell, but this is something you may have heard of on the news, and it’s really cool).

First a quick neuroscience lesson. Neurons can send electrical signals, and what starts these electrical signals is ions (which have a charge) moving into or out of the neuron. This happens when ion channels (they’re proteins that act as tunnels with gates that allow certain ions through when open) change shape to cause a pore to form. Two common examples of what could cause this shape change in neural ion channels is a molecule (termed a ligand) binding or by a voltage change. Below is a great image demonstrating how a voltage-gated ion channel works:

[Source]

But green algae and some bacteria also have ion channels that can be induced to change shape with certain wavelengths of light (actually some of your retinal cells can change shape in response to light, which is how you see! They’re called rhodopsins, but they aren’t ion channels and cause the light signal to be sent in a slightly different way).

That means that now you have a protein in one species that you can shine light on and cause it to allow the flow of ions. And you have neurons which “turn on” and “turn off” in response to ion flow. And with some genetic techniques that have been around for decades, we can actually cause these algal and bacterial proteins to be expressed in specific neurons in the lab! Which means you have precise control over when a certain group of neurons turn on or off! Below is a video of that in action. Note that when the blue light comes on, the mouse begins to run around the edges, which is very different from its behavior before and after.

Now this may seem a little creepy and over the top from just that video. But it’s not like we’re just around the corner from mind control. But it does allow us to study the neural circuits in lab animals. Because trying to study how all the billions of neurons in your brain work to coordinate movements and thoughts is incredibly difficult. Being able to turn on a specific group of neurons can begin to tell us which behaviors different ones are involved in, and therefore will help people piece together how they’re interconnected.

This tool has also been discussed in the treatment of diseases such as Parkinson’s. One issue in Parkinson’s is that you lose a certain group of neurons, but we know from other treatments (deep brain stimulation) that keeping the remaining neurons firing helps in managing the disease. So if you could implant a light to periodically turn on the neurons on the appropriate time, it could be therapeutic. The hard part is actually getting the proteins to be expressed (while we’re very good at genetic manipulations in research animals, gene therapy for humans isn’t quite here for the masses yet).

If you want to hear a little more (and put much more eloquently, haha), watch this Ted talk about optogenetics!

So that’s a popular example of how we can use proteins to precisely control a certain cellular function in order to study how something works! Which is basically what my project is doing, except we’re using light to control the production of proteins instead of using it to turn neurons on and off. But both are tools based off the fact that proteins have functions that are related to their shape, and we can use things like light to control the shape of certain proteins. Yay for biological tools! And yay for proteins!

Quick correction: I said what I’m doing is a bit different than optogenetics, which is actually incorrect. It falls under the heading of the term optogenetics. I had just only ever heard the term be used to specifically describe the method of using genetics to express light-sensitive ion channels, specifically. I wasn’t aware that it is used more generally to refer to using genetics to express any exogenous* protein you can manipulate with light.

*exogenous means non-native to the tissue/cell/organism. basically that the protein you’re expressing is not normally found there. Also just a reminder that if I ever use a term that makes you go, “wait, what the heck does that mean?” feel free to aks! Especially if googling isn’t helpful because 1) sometimes the use of a term in a specific sub-field is different than the common definition and 2) I use words wrong all the time, so it’s entirely possible I misused it. As in the case of optogenetics!

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