If you travel to the deepest, darkest depths of the ocean, you would find tiny glimpses of light. This light – known as bioluminescence – is produced and emitted by certain organisms and animals who carry it around in their bodies. Yes, they glow.
Jellyfish and fireflies, for example, are bioluminescent.
And Central Michigan University neuroscientist and College of Medicine faculty member Ute Hochgeschwender also is using their light to study how we may control — and ultimately repair — damaged cells in the brain and beyond.
Natural path to the brain
The concept of using light to control the activity of cells in the brain seems complicated – and it is – yet was made possible by something called optogenetics. As the term indicates, light is used to activate light-sensing proteins which are placed into specific cells in the brain by genetic engineering.
Depending on the type of protein, shining light on these cells can either activate or inhibit firing of neurons.
From the time it was introduced just over a decade ago, optogenetics has proven to be a powerful tool in the field of neuroscience. Yet it has limitations. One is that cells in optogenetic experiments can only be controlled by pulses of laser light, delivered through fiber optic wires placed into the brain.
"In a clinical context, long-term implants in the brain are highly problematic," Hochgeschwender said. "In addition, fiber optics can only reach a very limited number of cells – those very close to the tip of the fiber. Reaching cells dispersed throughout the brain would require inserting multiple fibers throughout the brain."
In 2013, while a faculty member at Duke University, Hochgeschwender discovered how these cells could produce their own light using — you guessed it — bioluminescence. Essentially, she enabled optogenetics research to go wireless.
Hochgeschwender's research showed by using this biological light source, neurons grown in dishes in the lab could be made to fire. This was the first step toward bioluminescence-driven optogenetics.
Taking back control
Taking the use of bioluminescence even further, Hochgeschwender and fellow researchers recently made
another exciting discovery, showing this biological light can be used to fire up or silence neurons in the brain of a moving animal.
The researchers used optogenetic probes attached to a luciferase — enzymes that produce bioluminescence when combined with a compound known as luciferin — to show the activity of neurons in separate regions of the mouse brain could be controlled by biological light. This resulted in turning the mouse around its axis either to the left or to the right.
"This discovery allows the arsenal of optogenetics to be complemented by a noninvasive approach for studies in freely behaving animals," Hochgeschwender said.
Hochgeschwender said this discovery could prove invaluable for experimental and clinical neuroscience – particularly for those researching treatment for diseases such as epilepsy and Parkinson's, where the neurons in the brain do not fire as they should.
"Using biological light, we can stimulate or silence specific cells in the brain simply by injecting the luciferin into the vein of the experimental animal, or ultimately, the patient."
Hochgeschwender and her team use a luciferase from the deep sea organism Gaussia Princeps, a cope pod, which uses a luciferin known as coelenterazine — or CTZ.
"Different luciferases emit different colors of light and Gaussia luciferase emits blue light," she said. "We need the blue light because the optogenetic elements are activated by light of the blue spectrum."
Taking it even further
A recently announced $1 million grant from the
W.M. Keck Foundation will allow Hochgeschwender and her students to join neuroscientists at Brown University to make bioluminescence-driven optogenetics, or BL-OG, even more powerful in the brain and beyond.
According to a story by Brown, lead researcher Christopher Moore, an associate professor of neuroscience at Brown, plans to use the grant to make cells "smart" enough to emit light precisely when needed in order to optogenetically control themselves or their neighbors.
Optogenetics has not yet been approved for use in humans. If it ever is, however, this new form of self-regulation could produce ways to treat not only epileptic seizures and Parkinson's disease but also diseases such as diabetes.
A conversation with neuroscientist Ute Hochgeschwender
How did you get involved in optogenetics research?
What made you decide to come to CMU?
"When I joined Duke University's neurobiology department in 2008, work in several laboratories there using optogenetic tools was in full swing. As I was in the process of refocusing my research toward studying the relationship of brain malfunction and behavior, incorporating means to modify neuronal activity in genetically defined cell populations in the brain of behaving animals was a great start."
In addition to technology development, I wanted to incorporate more aspects of applying the approaches we developed, specifically in neurodegenerative diseases. This is complementary to my colleagues' work in rat and mouse models of Huntington's, Parkinson's, Alzheimer's and other neurodegenerative diseases here in CMU's neuroscience program.
What opportunities do you and your students have through this revolutionary research?
"We are working on further expanding the concept of bioluminescence-driven optogenetics, as well as applying it to spinal cord injury models and to mouse models
of neuropsychiatric disorders."
What are your goals for the next five years through your research?
We aim to demonstrate applicability of our approach in manipulating transplanted stem cells, in stimulating neuronal regeneration in injury and in defining neuronal circuits affected in neuropsychiatric disorders.