Brain researchers study high-tech ways to overcome injury
About a year after winning a major share of a nearly $15-million grant, a team of Brown professors is developing and using new technologies to study the brain. Their goal is to inform the development of therapies that could restore functions lost to injury and stroke.
PROVIDENCE, R.I. [Brown University] — When six engineering and neuroscience professors took on Brown’s major role in the $14.9-million REPAIR project a little more than a year ago, they also took on a dream. Their goal is to understand the workings of the brain’s circuitry so well that it would be possible to fix a traumatic brain injury.
“The ability to help people who are severely disabled or injured in ways that no current medical treatment can cure is the dream,” said Arto Nurmikko, professor of engineering, who is the co-primary investigator of the project. It’s funded by the Defense Advanced Research Projects Agency, and is shared with Stanford University, the University of California–San Francisco and University College London.
New research to REPAIR the brain
The Brown team, which includes neuroscientists Rebecca Burwell, Barry Connors, John Donoghue, David Sheinberg, and Leigh Hochberg, hopes to ferret out how circuits of brain cells work to perceive the environment, process a physical response to it, and then command the body to act out that plan. For people who’ve suffered brain damage, the scientists’ goal will be to translate knowledge into treatments that can restore impaired functions.
“If there is an injury that leads to some kind of dysfunction in the brain, do we understand enough so as to substitute the missing part or the broken part with some of the kinds of the control technology we are trying to develop and replace that function?” Sheinberg said. “Do we understand how the visual system works well enough so that in the absence of a particular part of the visual system we can deliver signals artificially that might serve as a viable substitute?”
The goal is bold but the team is encouraged by the advent of a new technology called optogenetics. It allows them to genetically engineer brain cell circuits to be controlled with pulses of light. Blue light makes the cells active. Yellow light makes them inactive. The technology, developed by project collaborator Karl Deisseroth at Stanford, therefore allows scientists to control functions within the brain in the millisecond timescale of its natural operation. That technology, coupled with the traditional technique of reading out brain signals electrically, gives the researchers the ability to selectively change how brain cells are working and at the same time observe the response of connected cells.
“The optogenetic methodology is fairly new and it’s promising to revolutionize the experimental tools that we have for exploring how the brain processes information and remaps and reorganizes,” Burwell said. “This will be one way that we can target an individual neuron in order to change its patterns of activity. This would be the way that we write in a signal.”
To make such a read-write interface with the brain feasible, Nurmikko and his lab’s members in the first year have invented a new device they call the “optrode.” The prototype device delivers laser pulses to the brain to control circuits and records the electrical activity of neurons all within a wire comparable in width to a hair.
In experiments with rodents, Connors uses optogenetics to discern how individual cell behavior influences the operation of brain circuits, and Burwell is using optogenetics to study how brain circuits underlying functions such as attention and memory guide decision making and behavior. Sheinberg uses these methods to study visual perception and recognition, and Donoghue and Hochberg study how the brain produces physical movement commands. All together, the work will produce needed new findings in perception, cognition, and movement that can inform new therapies for people who have lost any of those functions to injury.
“There’s an awful lot to be learned,” Nurmikko said. “This paradigm of listening to the brain while actually informing the brain [with] methods that have not been available before, will elevate that understanding to a completely new level.”
By David Orenstein
PROVIDENCE, R.I. [Brown University] — When six engineering and neuroscience professors took on Brown’s major role in the $14.9-million REPAIR project a little more than a year ago, they also took on a dream. Their goal is to understand the workings of the brain’s circuitry so well that it would be possible to fix a traumatic brain injury.
“The ability to help people who are severely disabled or injured in ways that no current medical treatment can cure is the dream,” said Arto Nurmikko, professor of engineering, who is the co-primary investigator of the project. It’s funded by the Defense Advanced Research Projects Agency, and is shared with Stanford University, the University of California–San Francisco and University College London.
New research to REPAIR the brain
The Brown team, which includes neuroscientists Rebecca Burwell, Barry Connors, John Donoghue, David Sheinberg, and Leigh Hochberg, hopes to ferret out how circuits of brain cells work to perceive the environment, process a physical response to it, and then command the body to act out that plan. For people who’ve suffered brain damage, the scientists’ goal will be to translate knowledge into treatments that can restore impaired functions.
“If there is an injury that leads to some kind of dysfunction in the brain, do we understand enough so as to substitute the missing part or the broken part with some of the kinds of the control technology we are trying to develop and replace that function?” Sheinberg said. “Do we understand how the visual system works well enough so that in the absence of a particular part of the visual system we can deliver signals artificially that might serve as a viable substitute?”
The goal is bold but the team is encouraged by the advent of a new technology called optogenetics. It allows them to genetically engineer brain cell circuits to be controlled with pulses of light. Blue light makes the cells active. Yellow light makes them inactive. The technology, developed by project collaborator Karl Deisseroth at Stanford, therefore allows scientists to control functions within the brain in the millisecond timescale of its natural operation. That technology, coupled with the traditional technique of reading out brain signals electrically, gives the researchers the ability to selectively change how brain cells are working and at the same time observe the response of connected cells.
“The optogenetic methodology is fairly new and it’s promising to revolutionize the experimental tools that we have for exploring how the brain processes information and remaps and reorganizes,” Burwell said. “This will be one way that we can target an individual neuron in order to change its patterns of activity. This would be the way that we write in a signal.”
To make such a read-write interface with the brain feasible, Nurmikko and his lab’s members in the first year have invented a new device they call the “optrode.” The prototype device delivers laser pulses to the brain to control circuits and records the electrical activity of neurons all within a wire comparable in width to a hair.
In experiments with rodents, Connors uses optogenetics to discern how individual cell behavior influences the operation of brain circuits, and Burwell is using optogenetics to study how brain circuits underlying functions such as attention and memory guide decision making and behavior. Sheinberg uses these methods to study visual perception and recognition, and Donoghue and Hochberg study how the brain produces physical movement commands. All together, the work will produce needed new findings in perception, cognition, and movement that can inform new therapies for people who have lost any of those functions to injury.
“There’s an awful lot to be learned,” Nurmikko said. “This paradigm of listening to the brain while actually informing the brain [with] methods that have not been available before, will elevate that understanding to a completely new level.”
By David Orenstein
Why carbon nanotubes spell trouble for cells
PROVIDENCE, R.I. [Brown University] — It’s been long known that asbestos spells trouble for human cells. Scientists have seen cells stabbed with spiky, long asbestos fibers, and the image is gory: Part of the fiber is protruding from the cell, like a quivering arrow that’s found its mark.
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| Something perpendicular this way comesCells ingest things by engulfing them. When a long perpendicular fiber comes near, the cell senses only its tip, mistakes it for a sphere, and begins engulfing something too long to handle. Credit: Gao Lab/Brown University |
“It’s as if we would eat a lollipop that’s longer than us,” said Huajian Gao, professor of engineering at Brown and the paper’s corresponding author. “It would get stuck.”
The research is important because nanomaterials like carbon nanotubes have promise in medicine, such as acting as vehicles to transport drugs to specific cells or to specific locations in the human body. If scientists can fully understand how nanomaterials interact with cells, then they can conceivably design products that help cells rather than harm them.
“If we can fully understand (nanomaterial-cell dynamics), we can make other tubes that can control how cells interact with nanomaterials and not be toxic,” Gao said. “We ultimately want to stop the attraction between the nanotip and the cell.”
Misrecognition
Receptors on the cell’s surface crowd around the nanotube, effectively standing it upright. The cell mistakes the tube for a sphere and begins to engulf it.
Credit: Gao Lab/Brown University
Receptors on the cell’s surface crowd around the nanotube, effectively standing it upright. The cell mistakes the tube for a sphere and begins to engulf it.
Credit: Gao Lab/Brown University
Like asbestos fibers, commercially available carbon nanotubes and gold nanowires have rounded tips that often range from 10 to 100 nanometers in diameter. Size is important here; the diameter fits well within the cell’s parameters for what it can handle. Brushing up against the nanotube, special proteins called receptors on the cell spring into action, clustering and bending the membrane wall to wrap the cell around the nanotube tip in a sequence that the authors call “tip recognition.” As this occurs, the nanotube is tipped to a 90-degree angle, which reduces the amount of energy needed for the cell to engulf the particle.
Once the engulfing — endocytosis — begins, there is no turning back. Within minutes, the cell senses it can’t fully engulf the nanostructure and essentially dials 911. “At this stage, it’s too late,” Gao said. “It’s in trouble and calls for help, triggering an immune response that can cause repeated inflammation.”
The team hypothesized the interaction using coarse-grained molecular dynamic simulations and capped multiwalled carbon nanotubes. In experiments involving nanotubes and gold nanowires and mouse liver cells and human mesothelial cells, the nanomaterials entered the cells tip-first and at a 90-degree angle about 90 percent of the time, the researchers report.
“We thought the tube was going to lie on the cell membrane to obtain more binding sites. However, our simulations revealed the tube steadily rotating to a high-entry degree, with its tip being fully wrapped,” said Xinghua Shi, first author on the paper who earned his doctorate at Brown and is at the Chinese Academy of Sciences in Beijing. “It is counter-intuitive and is mainly due to the bending energy release as the membrane is wrapping the tube.”
The team would like to study whether nanotubes without rounded tips — or less rigid nanomaterials such as nanoribbons — pose the same dilemma for cells.
“Interestingly, if the rounded tip of a carbon nanotube is cut off (meaning the tube is open and hollow), the tube lies on the cell membrane, instead of entering the cell at a high-degree-angle," Shi said.
Agnes Kane, professor of pathology and laboratory medicine at Brown, is a corresponding author on the paper. Other authors include Annette von dem Bussche from the Department of Pathology and Laboratory Medicine at Brown and Robert Hurt from the Institute for Molecular and Nanoscale Innovation at Brown.
The National Science Foundation, the U.S. Department of Commerce National Institute of Standards and Technology, the National Institute of Environmental Health Sciences Superfund Research Program, and the American Recovery and Reinvestment Act funded the research.
By Richard Lewis