By Jill Sakai
Photography by Craig Mahaffey ’98 & Ashley Jones

Stephen Foulger is harnessing new X-ray-sensitive, light-emitting materials, which may enable control of neural activity from outside the skull

Before joining Clemson’s faculty in 1999, Stephen Foulger spent a stint working in the fiber optics industry. Years later, that background drew his interest to a developing field that uses implanted fibers to deliver light signals deep within the brain to trigger neural activity.

Called optogenetics, the experimental technique offers a way to change activity in targeted regions of the brain from outside the skull, using pulses of light delivered to light-sensitive proteins in the neurons. Researchers have tested the approach in animal models to try to restore activity in regions affected by neurodegenerative disease, for example, or to damp down errant neural firing in epilepsy. Foulger, the Gregg-Graniteville Endowed Chair and Professor of Materials Science and Engineering, marveled at the technique’s potential for exploring brain function or treating disease.

“These light-sensitive proteins open or close synapses,” he explains. “You can localize synaptic behavior in regions of the brain using these light-tunneling fibers and these proteins.”

But the need to implant the optical fibers directly into the brain is a major limitation of the technique’s broader use. Researchers must remove a small piece of skull and leave the fibers in place for the duration of an experiment.

With his expertise in designing optical materials, Foulger realized it should be possible to accomplish the task without fibers. He is now working to harness the potential of optogenetics for wider use by designing new light-producing materials that could make the approach noninvasive and bring it within reach for medical applications.

PARTICLE MAN

To accomplish his goal, Foulger is creating a completely new kind of bioimaging material.

“We’re trying to replace some of the fiber optic cabling that goes into the brain for optogenetics,” Foulger explains. “Instead of using fibers that go into the brain, we want to use radioluminescent particles and X-ray sources to generate light in these localized positions.”

The idea, he says, is to create tiny particles coated with light-producing materials that could then be injected via a shot and directed to infiltrate a targeted spot in the brain. When hit with a focused X-ray, the coating would emit light at a characteristic wavelength and activate nearby light-sensitive proteins, which change shape to drive neuronal firing.

Foulger and two collaborators, neuroscientists Lori McMahon at the University of Alabama at Birmingham and Jason Weick at the University of New Mexico, won a $6 million grant from the National Science Foundation to tackle this challenge. It’s a highly collaborative project designed to cross disciplines. Weick, a molecular biologist, is developing a method to get the light-sensitive proteins, called opsins, into brain cells. McMahon, a neurophysiologist, is exploring how to use X-ray-triggered particles to control brain circuits. And Foulger, as the materials scientist and director of Clemson’s Center for Optical Materials Science and Engineering, is responsible for creating the requisite particles. The NSF project naturally falls within COMSET’s scope of research on materials that generate, convey or manipulate light.

Ideally, the particles should be no more than 100 nanometers in diameter — roughly one-seventieth the width of a human hair — to pass through blood vessels and collect in the brain without causing damage. They need to work effectively in living tissue. And they must produce enough light to trigger the opsins, with as little X-ray exposure as possible.

“It’s a challenge,” Foulger says. “Making a sub-100-nanometer radioluminescent particle hasn’t been done. So, it’s a basic materials science problem.”

In the first years of the project, his group has successfully developed submicrometer ceramic particles doped with the rare earth element cerium and coated with light-emitting molecules called fluorophores. They are now testing materials with different emission wavelengths and characteristics — how much light the molecules produce and how well they pair with the sometimes-finicky absorption characteristics of the light-sensitive proteins called opsins. It can be a bit of a moving target, as opsin development is itself a complex, developing field.

“There are many kinds of these proteins, and they have different responses to light,” says McMahon. “We have to do a lot of testing to find out which light-sensitive protein and which of the particles that Dr. Foulger’s lab has made are the best ones to pair together.”

Foulger is now working to harness the potential of optogenetics for wider use by designing new light-producing materials that could make the approach noninvasive and bring it within reach for medical applications.

BRIDGING WORLDS

Although X-ray-sensitive particles exist for many industrial applications, developing radioluminescent materials compatible with living systems comes with a different set of challenges. Biological environments are wet, messy and unpredictable. Materials may behave differently in cells than in a chemistry lab, and differently in a whole animal than in a pile of cells. Or their function may change with long-term versus short-term use.

Creating something for use in a living body adds many extra constraints that the materials science world doesn’t always face.

“You don’t have a complete open palette of materials you’d like to use because of toxicity,” Foulger says. “A lot of the stuff that’s out there that’s radioluminescent is going to poison you, so we have a pretty tight constraint on what we can develop and put into a biological system. When we do simple toxicity tests with something new and we find that the cells don’t seem to respond negatively to it — to us, that can be a great day because it means we can keep going with the chemistry.”

For these considerations, Foulger has worked closely with McMahon and Weick. They quickly discovered that bridging disciplines also requires a bit of translation. “Initially, their definition of nontoxic and our definition of nontoxic were really different,” McMahon says, describing the need to keep neural cells not just alive but also healthy and unstressed. “It’s taken us some time to learn each other’s languages because our worlds are very different.”

With their combined expertise, they’ve progressed to early functional studies of the radioluminescent particles in rat brain slices — sections cut from a whole brain to retain some of the circuitry and function but in a preparation that can be studied in a lab dish.

The preliminary data are promising, McMahon says. The team has confirmed that neither the particles themselves nor X-rays at the needed dose hurt neural function. Now, she says, “we’re putting the particles from Dr. Foulger’s group on our brain slice, using X-rays and attempting to control circuits.”

For McMahon, it’s exciting to finally start seeing the nanomaterials and the physiology work together: “This is a project that we as neuroscientists would never do on our own, without Steve Foulger’s expertise. And he would never do this without our expertise.”

ONE STEP AT A TIME

The successes are encouraging but early steps on a long path, Foulger says. His group is continuing to refine the nanoparticles, adding different proteins to tune and enhance the light output. He’s also testing ways to help visualize the particles once in the brain since they’re too small to see with a light microscope.

At the same time, the Alabama researchers are working on how to get Foulger’s nanoparticles into an intact brain rather than slices. The brain is normally walled off from the rest of the body with the blood-brain barrier, a protective layer in blood vessels that keeps out immune cells, toxins and other potential threats. That means getting anything through — such as tiny manufactured particles — poses a significant challenge. McMahon’s group is working with focused ultrasound to transmit the particles through the vessel walls into the desired brain region.

Ultimately, the researchers hope to be able to inject the particles into the bloodstream, allow them to circulate to the brain’s blood vessels, then use focused ultrasound to open up the blood-brain barrier in a region called the hippocampus.

“We’re very interested in the hippocampus because that’s a part of the brain that’s required for learning and memory,” says McMahon. “The idea is to activate the particles to either turn on circuits to enhance learning or to use a different light-sensitive protein that would turn off circuits and prevent learning.”

This potential power of optogenetics to change behavior is part of what drew Foulger to the technique early on. While visiting a lab, “I saw rats that were addicted to cocaine or an opiate or something. They could hit a lever to get a dosage of the drug. And they would continue to do it until they basically had heart failure,” he recalls. “[The rats] had a fiber going to the brain in this certain region. … The animal’s hitting the lever, and the second [the researchers] fired up the laser and the light went in, … it shut down that addiction zone in the brain. The animal just stopped. It was mind-blowing.”

Foulger hopes that someday his work could lead to a technique that could reset brain circuits to help people unlearn unwanted patterns such as substance abuse or trauma or regain function in damaged pathways.

“That’s way down the road,” he says. “But it’s why we’re moving down this path.”

Jill Sakai is a freelance writer in Wisconsin.

1 reply
  1. Gene Alford, MD says:

    I graduated from Clemson and practiced Ophthalmology for many years in Houston, Texas. I was wondering if you have considered using the light sensitive proteins in the retina rods and cones. A wave length in the visual spectrum would probably be needed besides x-rays. If they could be implanted in the occipital cortex and stimulated to produce light perception, that would be a wonderful thing for a blind person that has no light perception. A receptor placed on the skull and connected to a transmitting wire going to the occipital cortex could possibly transmit wave lengths in the visual spectrum. Possibly some other way to do it. Thanks. Gene Alford, MD. ‘57 in Textile Chemistry

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