Neuroscience may be the most metaphysical specialty in modern medicine. After all, when the scientific mind turns inward it ends up matching wits with itself, pitting neural matter against neurons. The result is a fascinating dialogue where the brain becomes subject, object, and verb all at once. Heady stuff . . . yet this is no mere exercise in philosophy. Hidden within the folds are the answers to some of our most devastating diseases, including schizophrenia and autism, Parkinson’s and Alzheimer’s. It’s the job of the neuroscientist to make the journey of discovery to seek them out.
As French anthropologist Claude Lévi-Strauss once said, “The scientific mind does not so much provide the right answers as ask the right questions.” In other words, there is often a great deal of art in neuroscience.
UAB psychiatry chair James Meador-Woodruff, M.D., is eavesdropping on the brain’s chemical communication system, listening for clues to the garbled messages responsible for schizophrenia. Nearby, neurology chair Ray Watts, M.D., is testing a dozen new treatments for Parkinson’s disease, including a novel form of neural gardening that transplants healthy dopamine-producing cells from the retina into the fallow ground of the striatum. Just down the street, David Sweatt, Ph.D., chair of neurobiology, is using Lego bricks to tease the secrets of memory loss from the minds of mice. Elsewhere on the UAB campus, David Standaert, M.D., Ph.D., is taking the measure of a toxic protein implicated in both Parkinson’s and Alzheimer’s. A giant scorpion is helping Harald Sontheimer, Ph.D., defend the brain from invading tumors. And Kevin Roth, M.D., Ph.D., is testing the delicate balance between life and death in neural cells.
These researchers are some of the leading actors in an all-star cast that is launching UAB neuroscience onto the world stage. Studies in their departments could provide revolutionary treatments for diseases that affect one in three Americans. “I feel fortunate to be at this point in history,” says Sweatt. “The next 50 years are going to be the golden era of neuroscience.” Sweatt and his colleagues have all made their own pioneering contributions to the field, but along the way they have learned that neuroscience is a lot like show business: Talent and hard work are crucial, but the secret to success is in who you know.
Neural Networking
Enter the new UAB Comprehensive Neuroscience Center (CNC). Its mission is to assemble a talented cast of clinician-scientists, give them space to work, attract funding for cutting-edge equipment, then scoop up pieces of brilliant research from across campus and send them speeding from laboratory bench to clinical trial to hospital bedside. “UAB is the first institution in the country to put together a truly comprehensive approach to the neurosciences,” says Sweatt. “The whole thing sounds like an administrative geek’s dream, but it’s really working.”
Kevin Roth’s job is to keep it working. Roth is the prototypical neuroscientist, an M.D./Ph.D. whose studies of neural cell death could lead to new drug therapies for a host of neurological conditions, including brain tumors, Parkinson’s, and Alzheimer’s.
“Our understanding of how the brain and mind work is on the threshold of major advance, with implications for many of the most important neurological and psychiatric diseases.”
—Dean Robert Rich |
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In addition to his duties as the neuropathology division director, he has assumed a larger role as founding director of the Comprehensive Neuroscience Center. That makes him the university’s resident scientific matchmaker, charged with connecting the dots among neuroscience research teams spread across seven of UAB’s 12 schools. “There’s neuroscience going on in almost every building on campus,” says Roth, “and we want vision scientists, psychologists, biomedical engineers—everybody at UAB who consider themselves neuroscientists—to join us.”
“Kevin is Dr. Neuroscience,” says Meador-Woodruff. “Whenever I hire new researchers, I bring them to see him, and he always says, ‘There’s somebody you don’t know yet that you need to meet,’ and sure enough it’s a great fit.”
Solving the Mind-Body Problem
Meador-Woodruff has hired quite a few new researchers lately. He has created a major schizophrenia research program in the psychiatry department, and he plans to expand research in mood disorders, substance abuse, disorders of childhood, and disorders of the elderly. That will require more high-level recruiting, and Meador-Woodruff says he is encouraged by the support he’s found in the Comprehensive Neuroscience Center.
“Each month, the department and center chairs meet to catch up on each other’s research and find out whom we’re trying to recruit,” he says. “We’re all looking for synergies and ways to share resources to make those synergies happen.”
President Carol Z. Garrison, Ph.D., and School of Medicine dean Robert R. Rich, M.D., have made it clear that UAB will continue investing heavily in the resources necessary to transform UAB into a regional neuroscience hub. Hundreds of thousands of square feet of new and revamped laboratory space have opened in recent years, and aggressive recruitment efforts are building a dream team of researchers. “This has become an exciting place to do neuroscience,” Roth says. “Almost every week I hear about another world-class investigator coming to UAB.”
 Many of these investigators bring along substantial federal funding, and the National Institutes of Health (NIH) also has contributed directly, awarding UAB one of its highly competitive Blueprint for Neuroscience Research grants. “I knew this was an area of major opportunity for UAB, both for scientific advancement and NIH funding,” says Dean Rich. “So I was quite determined to make neuroscience a priority from the day I arrived.”
The Comprehensive Neuroscience Center concept was born out of the schoolwide strategic planning initiative that Rich began soon after coming to UAB from Emory University in 2004. Based on the Comprehensive Cancer Center’s successful model, it will bring together practicing physicians and basic scientists to blaze a path from molecular studies to usable treatments. Indeed, a few minutes in the labs and clinics of UAB’s top neuroscientists reveals how far along that path they have come—along with tantalizing glimpses of the future of medical care.
Trials by Fire
Ray Watts, who chairs the Department of Neurology and directs clinical research in the Parkinson’s Disease and Movement Disorder Research Program, has built up a group of investigators who identify promising laboratory discoveries and usher them into the crucible of the clinic.
Two of his most intriguing current projects capitalize on the brain’s amazing plasticity—a quality that remained unknown until quite recently. In the Seragene gene therapy trial, researchers are using a series of carefully placed injections to slip a common virus past the blood-brain barrier. Once inside, the virus delivers its payload: a strong growth factor designed to protect and revive the dying dopamine cells that are the root cause of Parkinson’s symptoms.
Another multicenter study is testing the effectiveness of transplanting retinal epithelial cells into the striatum as a replacement for the brain’s lost dopamine. “The exciting thing is that these treatments have the potential to restore function,” says Watts. “A decade or two ago, to think about restoring lost function in a progressive neurological disorder would have been fantasy.”
 In order to keep the pipeline stocked with potential new treatments, Watts actively recruited David Standaert from Harvard University to direct UAB’s Division of Movement Disorders and the new Center for Neurodegeneration and Experimental Therapeutics. While he wasn’t looking to leave Harvard, Standaert quickly realized that he “had the opportunity to do something really extraordinary here,” he says. “Neuroscience at UAB offers an expanding universe of science and clinical care, and there are so many things you can do in an expanding universe that you can’t do in a static environment.”
His mission in that expanding universe is to recruit a team of basic-science investigators who can “synergize with the clinical work,” Standaert says. “We’re building a group that is really focused on delivering therapies to the clinic that can be used to treat patients relatively quickly.”
Standaert’s lab focuses primarily on synuclein, a protein whose overexpression in the brain is strongly linked to the onset of Parkinson’s disease. “We’re trying to understand more about why synuclein is toxic and how we might modify that toxicity,” he says. That could lead to new compounds aimed at preventing overexpression of the protein or speeding up the mechanisms by which it is removed from the brain.
Circuits to Clinics
While Watts and Standaert open new fronts in the war on Parkinson’s, James Meador-Woodruff is building his forces for a major assault on schizophrenia. The new chair of the Department of Psychiatry and Behavioral Neurobiology gained international recognition at the University of Michigan for his research on signaling mechanisms in the healthy brain and the ways those signals go awry in schizophrenia patients. He is expanding this work at UAB and delving into new areas with a recruiting blitz that added seven faculty and two postdoctoral schizophrenia researchers in seven months.
One of these new arrivals, Rosalinda Roberts, Ph.D., is building a “brain bank” that will greatly facilitate psychiatric investigation, says Meador-Woodruff. In keeping with UAB neuroscience’s translational mission, other recruits will “take our findings at the cellular level and create hypotheses that are testable in living patients,” he explains. Using the new functional magnetic resonance imaging (fMRI) machine at UAB’s Civitan International Research Center and tests developed in the psychology department, researcher Adrienne Lahti, Ph.D., can scan the brains of schizophrenic patients in UAB’s community health psychiatry program for clues indicating which specific treatment will work best in each patient’s case.
“It’s the UAB philosophy in a nutshell,” Meador-Woodruff says. “She has her magnet, and my people have their test tubes; this opportunity came up for us to partner, we brought in people from other departments, and now we have a campuswide collaboration.”
The Magic Memory Pill
As new investigative teams descend on Birmingham with precious research in tow, each faces the challenge of integrating itself into the spinning engine of UAB’s neuroscience machine. That’s a particular problem for a senior researcher such as David Sweatt, who left Baylor University last spring to become chair of the Department of Neurobiology and director of UAB’s Evelyn F. McKnight Brain Institute. “It’s something every scientist worries about,” he says. “But I think we’ve probably made the most important discoveries of my entire career in the few months we’ve been at UAB.”
 Sweatt’s research team studies how the brain stores long-term memories, then applies that knowledge to conditions such as learning disorders and aging-related memory dysfunction. Lately, they have spent a lot of time pondering the field of epigenetics. Epigenetic mechanisms are critical in the body’s development—they give embryonic stem cells their marching orders, directing some to become liver cells, others to become brain cells, and so on. The cells are able to “remember” their new role for life, and Sweatt’s team has been hoping they might offer insights into adult learning and memory.
At UAB it all came together. “We’ve found that, just as with epigenetic mechanisms, adult learning causes changes in the physical and chemical structure of DNA,” says Sweatt. “We’ve discovered that a component of the mechanisms that allow you to learn a piece of information and put it in long-term memory represents a change in the actual three-dimensional structure of DNA in the brain. That’s fascinating; it would really have sounded like science fiction five years ago.”
These learning mechanisms may be disrupted in patients with memory disorders, so Sweatt’s group set about developing compounds with the potential to reverse the damage. Early tests in mice have shown a “pronounced increase in memory robustness,” he says. “This might allow us to design new therapies for aging-related dysfunction, Alzheimer’s disease, and mental retardation syndromes.” Indeed, he says, future tests could produce a drug that not only restores memory levels to normal but actually improves them.
Secrets of a Sleeper Cell
Basic scientists don’t often get the chance to take their research from molecule to medication, but Sweatt’s fellow neurobiologist Harald Sontheimer has done it twice, in colorful fashion. Sontheimer is director of UAB’s Civitan International Research Center, but he also leads the university’s new Center for Glial Biology in Medicine, the first research enterprise dedicated to the glial cell, a long unappreciated neural cell whose name is derived from the Greek word for glue.
“We’ve probably made the most important discoveries of my entire career in the few months we’ve been at UAB.”
—David Sweatt |
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“About half of our brains are filled with glial cells, but they were thought to be just connective tissue; for the longest time we really had very little knowledge about what they do,” Sontheimer says. Over the past 20 years, he has taken part in most of the research pinpointing a leading role for glial cells in the development of brain tumors, as well as multiple sclerosis, epilepsy, Parkinson’s disease, and chronic back pain.
“Primary brain tumors are almost always derived from glial cells, and that is a mainstay of study in our laboratory,” says Sontheimer. His research team discovered a weakness on the surface of glial tumor cells, then extracted a drug from scorpion venom that exploits this weakness and stops the cells from invading the brain. Sontheimer recently found another way to control glial-derived brain tumors in a similarly unlikely source: an FDA-approved medication for Crohn’s disease called sulfasalazine. A controlled clinical study could soon make this a primary treatment for patients with glial tumors.
World Without Walls
Even outside the world of glial biology, Sontheimer knows a thing or two about connective tissue. He is excited about the Civitan International Research Center’s role in supporting UAB’s broad neuroscience efforts, which includes opening its new fMRI machine to researchers across campus. He also notes that the center’s long track record of bringing together like-minded investigators offers valuable lessons on the best ways to encourage meaningful collaboration. “One of the strategies we have used is to put people with similar disease interests in proximity, even if they’re not in the same specialty,” he explains. “Once you do that, a lot of interaction happens naturally.”
Natural interaction has been a frequent topic on Kevin Roth’s mind. He is confident that the Comprehensive Neuroscience Center can succeed by convincing researchers to look up from their own work and see the possibilities in collaboration. “That way people will understand that what’s good for Alzheimer’s research isn’t bad for psychiatric research, for example,” he says. “These diseases all interact, and by generating a culture where the scientists know and talk to each other, we will more rapidly develop cures or preventions.”
Dean Rich emphasizes that neuroscience research will remain a top priority for the School of Medicine. “Our understanding of how the brain and mind work is on the threshold of major advance, with implications for many of the most important neurological and psychiatric diseases,” he says. “I want UAB to participate in those advances.”
And as the Comprehensive Neuroscience Center blossoms, Roth says, the entire community will share in the fruits. “We hope to add 50 new faculty in the next five years, and they will bring grants with them and hire support staff,” he explains. “There will be interest in forming biotech companies based on their research, as well as interest from drug companies on collaboration for new therapies. I think we can become a real powerhouse in the Southeast.”
UAB and other institutions can’t afford not to invest in fighting neurological and psychiatric diseases, adds Roth: Treatment costs currently run to $500 billion per year in the United States alone. “It’s just like the days of the polio epidemic,” he says. “They had a choice: Buy more iron lungs, or invest in a cure to prevent polio in the first place. We’re in the same position. Neuroscience research has gained momentum, the door has opened a crack, and we’re trying to bust it down the rest of the way.”
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