Listening in on the Brain
New Technologies to Fight Neurological Disorders
Can the technology that created the microchip help to restore motor function to people with Parkinson's disease? Greg Gerhardt at the University of Kentucky thinks so, and he's designing high-tech microsensors and electrodes that may one day allow doctors to deliver powerful proteins directly to the brain to treat people with devastating neurological disorders.
Though today's most advanced microchips bear only a vague resemblance to the mysterious circuitry inside our heads, Gerhardt is using this technology to eavesdrop on the brain's most vital communications. Microchips are created with photolithography, a process in which photosensitive film is exposed to ultraviolet light to produce a pattern on a thin wafer. "Our newest sensors are patterned with photolithography onto small ceramic wafers, cut out with lasers, and microbonded to a microelectrode holder," says Gerhardt, who came to UK in 1999 and is director of the Center for Sensor Technology.
Gerhardt is using microsensors and electrodes to eavesdrop on the brain's most vital communications.
"Biology is chemical communication, and if you want to understand biology you have to understand chemical communication between cells. These sensors can give us new insights into how the nervous system works. We can count the number of molecules on the surface of the sensor very rapidly and what that allows us to do is literally listen as brain cells communicate with each other," says Gerhardt, a professor in the UK College of Medicine Department of Anatomy and Neurobiology.
The sensors are very tiny, about half the thickness of a human hair. (A human hair is approximately 0.003 inches or 75 microns.) These microelectrodes can be implanted in various regions of the brain to measure neurotransmittersmolecules involved in brain signalingwhich include dopamine, norepinephrine, serotonin, glutamate, and nitric oxide. Previous studies in animals have revealed that disruption of dopamine regulation in the brain is the primary cause of the movement problems associated with drug-induced Parkinson's disease.
For his study of Parkinson's, Gerhardt has designed sensors with a thin polymer coating that attract dopamine molecules. "The polymer is negatively charged so it attracts positively charged molecules," he explains. "When dopamine touches the electrode's surface by going through that nanometer-thick polymer film, the sensor makes the molecule oxidize, or lose electrons; then the sensor counts the electrons from the oxidation." The number of electrons directly relates to the number of the molecules present. This electrochemical process happens very rapidly, Gerhardt says. Just as quickly as it is oxidized, the sensor gives back electrons to the molecule.
"The sensor counts only the molecules that touch it, a fact that gives us tremendous capability to map how brain circuitry works," he says.
Greg Gerhardt, who came to UK in 1999 from the University of Colorado, is director of the Center for Sensor Technology.
Gerhardt's research team has already tested these sensors by "listening in" on brain activity in animals with drug-induced Parkinson's disease. Implanted sensors allow researchers to monitor what is going on in the animals' brains while they are in motion and at rest. "We've discovered that these procedures are relatively non-invasive, because they cause minimal damage to brain tissue, and they're safe," he says. In creating these sensors, Gerhardt explains, he's tapped into a whole field of science focused on identifying "biocompatible materials," materials that won't set off inflammatory responses in human tissue.
Gerhardt's sensors involve microcabling and small devices called headstages that process the information from the sensors very close to the source. Headstages range in size from a few centimeters to about the size of a deck of cards and are composed of a small computer chip and a cable connection. These devices do the initial signal transformation; they convert data from the sensor into electronic signals the computer can process. (Gerhardt points out that with modern electronics it's possible to do all the data processing on the sensor itself, but right now that's too expensive.)
Measurements that once required a multitude of scientific instruments are now all handled in one computer software program. "You literally just push a button and the computer takes over," Gerhardt says. "One of our latest technologies is going to be marketed in the $12,000 range. It includes an integrated system that plugs into a modern Pentium computer and all the necessary hardware and software to carry out the measurements from these microsensors."
Gerhardt's first sensors cost him $10,000 each. "But now we've already dropped that cost to about $100, and I expect the cost will decrease to more like $25 a piece once we start to mass-produce them," he says.
"We need to educate people that this is a device that is best used and then thrown awaya fact which should make it very popular in the United States," Gerhardt says, slightly tongue-in-cheek. "It's disposable."
"After a while white blood cells, red blood cells, and proteins stick to the surface of the sensor and interfere with the signaling process," he explains. "There's an enormous amount of science going on right now looking at modifying surfaces so that they're less prone to 'foul.' Essentially what we're talking about is poisoningthe biology poisons the electrode." Gerhardt says in the first few hours after a sensor is implanted it loses about 10 to 20 percent of its sensitivity because of rapid adsorption of certain brain proteins. "The polymer coating we use has extended the lifespan of our sensors. We can record in the brain for weeks, perhaps even months, but in the future we'd like to record in animals and humans for years."
Interest in improved polymer coatings reaches far beyond scientists working on brain signaling, Gerhardt says. Right now researchers are working on coatings for cars that would mean the death of the car wash. Imagine a coating that would prevent dirt from sticking to the surface. Imagine the popularity of a car that washes itself in the rain, Gerhardt says. "If we get to a point where we don't have leaves and dirt sticking to our cars, surely we can put some of that technology to use in tissue or our blood-stream."
Drug Delivery to the Brain
Parkinson's, a disease that affects more than a million people in North America, progressively impairs control of body movement and often leads to immobility. Although current treatments with oral medications can almost completely restore normal movement to people in the early stages of Parkinson's, the drugs lose effectiveness as the disease progresses.
"If we could treat the disease throughout the lifespan of the individual as well as it's treated in the first three years with these medications, we quite frankly wouldn't need to be doing this research," Gerhardt says. But medications have side effects, and not all patients respond to the drugs. "We can currently treat the disease, but that doesn't mean the person's life is like it was before they developed Parkinson's." He says quality of life, after all, should be the ultimate concern.
Improving the quality of life for people with Parkinson's disease has been a career-long goal for Don Gash, chair of UK's anatomy and neurobiology department. He has studied Parkinson's in animal models since 1985.
"In the mid-'80s, researchers were trying to leap directly from rodent studies to humans," says Gash. "A human brain is approximately 1,300 grams; a rat's brain is about one gram. We need to know how to translate rat data to the larger human brain context. This scaling up is critical as you're trying to work out new therapies," he says.
Gash and Gerhardt have known each other for nearly 20 years, but it wasn't until 1991 when Gash was working at the University of Rochester and Gerhardt was at the University of Colorado that they officially began to collaborate. When Gash joined the UK faculty in 1993, Gerhardt began traveling to Kentucky to continue their work, and in 1995 Gerhardt became a visiting scientist in the anatomy and neurobiology department.
Gerhardt was recruited to UK under the initial phase of the Research Challenge Trust Fund (RCTF) program established by the 1997 Kentucky Postsecondary Education Act. This phase of RCTF included $16 million to support new faculty, graduate students and staff. "The Research Challenge Trust Fund allowed us to put together the resources to enable Greg to do research here that would be hard to do elsewhere," Gash says, attributing UK's MRI (magnetic resonance imaging) and animal research capabilities as strong lures. Gerhardt says the RCTF program provided exactly what he neededa faculty position, start-up funding, and good research space.
In 1999 Gash and Gerhardt's collaboration led to a five-year, $5 million grant from the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health. The NINDS grant established a Morris K. Udall Parkinson's Disease Research Center of Excellence at UK, one of only eight centers funded that year.
The grant supports a collaborative project by Gerhardt, Gash and Zhiming Zhang that will lay the foundation for a new therapy for Parkinson's diseasedirect delivery of a key protein to the brain to repair damaged cells. This research is focused on a protein called glial cell-line derived neurotrophic factor (GDNF). "Trophic factors are proteins manufactured by cells, often used in cell programming, differentiation, growth, and maintenance," Gerhardt explains. "Perhaps the most widely studied is Nerve Growth Factor or NGF. Lack of that protein seems to play a fundamental role in Alzheimer's disease."
GDNF is found in low levels in the adult human brain and may allow these researchers to "turn back the clock" on dopamine neurons sabotaged by Parkinson's. "If we re-administer this protein in an adult brain that's damaged, it looks like we can potentially arrest further degeneration and even repair some of those neurons," says Gerhardt.
Gash attributes UK's success in attracting the NINDS grant to the team's unique combination of expertise. "It's a credit to the team. Each person brings a number of strengths into this," he says.
"Greg's skills in electrochemistry are unique in a lot of ways. He's viewed by his peers as a very productive and original thinker at the cutting-edge of developing sensor technology and adapting it for use in studying the brain. He blends his expertise in analytical chemistry with insights into modern questions in neurobiology, an unusual combination," says Gash.
"Greg has the capabilities to figure out what is going on in the brain using neurochemistry, and Zhiming Zhang, a neurosurgeon from China, uses MRI and is working on site-specific delivery of trophic factorswhich we think is the key to using these factors to treat Parkinson's. Collectively, our team is able to do functional neuroanatomy at a level that's really not possible at many other places in the world," Gash says.
The team's research is focused on modifying the Medtronic SynchroMed® Infusion System, an implantable and programmable pump, to deliver drugs directly to the brain. Medtronic Inc., based in Minneapolis, Minnesota, is an international medical technology company known for its pacemakers. Medtronic began working with Gerhardt and his Center for Sensor Technology at the suggestion of the National Science Foundation in 1994.
Dennis Elsberry, a technical fellow in Medtronic's drug delivery venture area who holds 16 patents, says the company finds collaboration with academic researchers advantageous. "What we try to do in selecting academic institutions is to leverage the specific research capability they have to address the questions we need to have answered with regard to establishing the safety of delivery to the central nervous system," he says.
Elsberry's research in the 1980s led to the development of the SynchroMed pump, a device that is currently approved to deliver drugs directly to the fluid around the spinal cord in patients with chronic and intractable pain, cancer pain, and severe muscle spasticity, as well as deliver chemotherapy agents to treat colorectal cancer that has spread to the liver.
"This self-contained, computer-controlled, stainless steel pump is about the size of a hockey puck," Gerhardt says. "It works via a principle called peristalsis. It has a little motor and a wheel that pinches tubing to move fluid through a plastic line." The pump is refilled each month and has a battery that lasts for three years. "It's computer programmable with a wand, which means you can reprogram it across the skin." Drugs travel from the pump, often implanted in the abdomen, through small tubes placed under the skin to the tiny device the UK team is designing that will allow drugs to flow into the brain.
"What we're developing are miniature tubes that can be inserted directly into the brain to administer proteins like GDNF," says Gerhardt. "This collaboration with Medtronic is laying the foundation for not only administering GDNF, but also a whole host of other drugs that can't be swallowed or injected into the bloodstream for the treatment of a variety of brain disorders."
Stewart Surgener, a UK grad and research analyst in Gerhardt's laboratory, uses HPLC (High-Performance Liquid Chromatography) to study neurotransmitters in brain samples.
One advantage of direct-delivery technology is that proteins will be able to bypass the blood-brain barrier. "The blood-brain barrier is not really a physical barrier," says Gerhardt. "It involves the fact that not all molecules or drugs can penetrate the brain from blood vessels." He says there's a lot scientists have yet to learn about this barrier, but it's clear that many drugs or proteins, like GDNF, can't cross it.
This technology will also eliminate potential side effects because drugs will be delivered only to the damaged neurons. Gerhardt says GDNF and similar proteins have a variety of effects on other systems within the body, which automatically rule out giving drugs orally. "For example, GDNF is involved in the normal development of your kidneys," he says. "If we made an oral drug today that activates the systems this protein normally activates, we'd probably set off so many side effects it could be catastrophic."
Gerhardt points out that the biggest challenge to this new technology is fear. "Most people don't want to have us stick a tube in their brain. But the reality is that the medical community has very successfully been putting tubes in the human brain for about 80 years. While it sounds a little like something out of Star Trek, the insertion of tubesmost clinicians refer to them as shuntsis actually a very safe procedure," Gerhardt says.
"I've talked to patients with Parkinson's, and this concept doesn't seem to bother them, because, after all, they're living with the disease. It's the family members of the patients who say, "You're going to put a tube in his brain? Can't you do something else?' So we'll have to educate people that if there were any other way to do this, we certainly would. This is the safest method to deliver these very powerful proteins."
This research is currently in the preclinical stage. "We're pushing forward to gain safety data so we can go to the FDA, and, we hope, carry out a clinical trial here in the next several years," Gerhardt says. The team is gathering that data based on the technological contributions of Amgen and Medtronic provided at no cost to UK. Amgen, an international drug company headquartered in California that makes GDNF from E-coli, is supplying UK with the purified protein.
"Medtronic has provided us with pumps, associated technology and technical support that would have cost us hundreds of thousands of dollars. The pumps themselves used clinically are valued at $10,000 each, and we have 20 animals with these pumps. Medtronic has given us $200,000-plus in product, not counting the computer to program the pumps," Gerhardt says.
"Without cooperation from Medtronic and Amgen and a whole host of other companies and biotech firms, it would be another three or four years before we could even begin thinking about clinical trials," he says.
Success in adapting this direct-delivery pump may have a ripple effect on technology and medicine, says Gerhardt.
"It's not inconceivable to think of a pump that would eventually fit behind your ear, like a hearing aid. Every day we use technology that's more complicated than this little pump, and the reason we can afford it is millions of people are buying the technology," he says. "If we can prove this technology has widespread use, we can look forward to a whole new generation of micromachines that will revolutionize the way we treat diseases."
Left to right: Greg Gerhardt (director of the Morris K. Udall Parkinson's Disease Research Center of Excellence at UK, and director of the Center for Sensor Technology), Don Gash (Alumni Chair in Anatomy and Neurobiology, and director of the Magnetic Resonance Imaging and Spectroscopy Center), Byron Young (Johnston-Wright Endowed Chair of Surgery, and chief of staff of the University of Kentucky Hospital), and John Slevin (principal investigator for the clinical trial, and director of the UK Movement Disorders Clinic).
On March 18 in Lexington, Kentucky, this team of researchers began a clinical trial to determine the safety of a new treatment for Parkinson's disease. This treatment, which involves direct delivery of the protein GDNF to the brain through an implanted pump, may be the first to restore brain function by targeting impaired neurons. (Current treatments are effective at improving symptoms for a limited time.) This clinical trial will follow 10 patients for nine months. Efficacy trials, with a much larger pool of patients will follow.