Brain Gain

Human Brain Lab Enables Studies of Living Tissue

Perhaps the workings of the human brain are most appreciated when they falter.

Disrupted blood flow in the form of a stroke or aneurysm can cause paralysis, speech loss and other profound disabilities. The inexplicable formation of plaques and tangles causes the memory-robbing disease, Alzheimer’s. Misfiring neurons can lead to seizures. Insufficient dopamine can cause conditions as diverse as depression and Parkinson’s disease.

A well-functioning brain is poetry in motion—a sentiment uttered, a task completed, a life lived. A diseased or injured brain can bring that life to a screeching halt, either through death or disability.

The Medical College of Georgia is better-equipped than ever to probe the intricacies of the brain—remarkably, by studying living human brain tissue that lies in Petrie dishes on campus.

MCG is one of only a few institutions worldwide housing a Human Brain Lab. The lab, which opened in 2004, primarily houses tissue dissected from the brains of patients with seizures that don’t respond to medication. The tissue represents the portion of the brain where neurons misfire. If it is determined to be non-crucial to critical functions such as speech and reasoning, it can often be safely removed without impairing the patient, while minimizing or eliminating seizures in the process.

Dr. Sergei Kirov, director of the lab and assistant professor of neurosurgery, works closely with MCG neurosurgeons so he or an assistant can join them in the operating room when the tissue is removed. “To date, we have acquired considerable experience collecting tissue in the operating room,” Dr. Kirov said.

The tissue is placed in sterile oxygenated fluid that simulates cerebrospinal fluid, transported to the adjacent Human Brain Lab and cut into tiny slices for optimal preservation. The slices are used within 24 hours or placed in a tissue culture incubator where they can survive several weeks. The tissue lacks a blood supply but otherwise functions largely as it would naturally. Scientists can not only observe that function, but can inject genes and drugs, dissect different portions and otherwise manipulate the tissue to better understand how it works.

For instance, Dr. Cesario Borlongan, associate professor of neurology, has transplanted stem cells into the tissue to study their proliferation, differentiation and interaction with neuronal networks and glial cells, specialized cells that surround neurons and affect their communication. Dr. Kirov is probing whether the faulty activation of astroglial cells contributes to epilepsy. He and Dr. Ioulia Fomitcheva, assistant research scientist in neurosurgery, are studying reelin, a protein in the brain, to gauge its function and possible role in epilepsy. Dr. William Hill, associate professor of neurology, is identifying the molecular profile of cells in brain blood vessel walls to develop therapies for brain disorders such as stroke and tumors. Dr. David Hess, professor and chair of neurology, is adding drugs to the tissue, including the antibiotic minocycline, to determine possible treatments to minimize brain damage after a stroke.

Stroke has particularly urgent ramifications, the researchers said, noting the disease is a major cause of death and disability in the United States but stubbornly resistant to treatment. The disease sets in motion a “death wave” that over hours and even days emanates from the original site of the blood loss to surrounding tissue, exacerbating brain damage as it expands.

The clot-busting drug, tissue plasminogen activator (tPA), can help halt the death wave and minimize brain damage, but only if administered within hours of the stroke. Complicating matters are the drug’s scarcity in many rural areas and many physicians’ lack of training in its use. “Only 2 percent of patients receive tPA, and the window is only three hours,” Dr. Kirov said. “It’s not possible to deliver it in time in most cases, and it is associated with a substantial risk of intracranial hemorrhage, so side effects can be significant.”

MCG is addressing these problems by working closely with rural hospitals in the use of tPA, but new solutions are urgently needed. Human Brain Lab studies offer potential new avenues for hope.

“The lab has provided access to human brain tissue that would otherwise be very difficult to obtain,” Dr. Hill said. “It has also provided access to collaborators who bring new approaches into stroke research. We can now look at real-time changes in brain following stroke injury.”

Dr. Hess concurs. “The lab allows us to study live human tissue in its real architecture.” He is particularly excited about techniques Dr. Kirov has developed enabling study of how dendritic spines respond to disrupted blood flow.
“The brain lab offers us unique opportunities to help translate basic research findings into an understanding of clinically important problems,” Dr. Kirov said.

Dr. Cargill Alleyne, chair of the Department of Neurosurgery, agrees. “I think it’s an innovative way to study clinical material,” he said. “It’s one of the best examples of translational clinical research, taking a patient specimen and studying the live tissue in a lab to elucidate the mechanisms of diseases such as epilepsy and stroke. I think it represents a great opportunity to further the knowledge base for these diseases.”

Yet Dr. Kirov emphasizes that the lab merely supplements, rather than replaces, more conventional forms of research, such as studies of laboratory animals. “Human tissue won’t replace animal models,” he said. “You have more control with animals. You can plan studies and repeat them. But human tissue offers an opportunity to check a hypothesis: Are we on track or completely off base? Human tissue offers a way to validate animal models and provides a translational bridge between animal and human studies.”

He also notes that what is true of, say, a rat brain, may hold little significance for a human brain. “So many drugs are neuroprotective in animals but don’t work in humans,” he said.

And he has no doubt that studies of human tissue will raise many more questions than they answer. That, he said, is why he loves studying the brain in the first place. “The brain has so many different neurons, so many different cells,” he said. “It’s a fascinating structure. We know five times more now about how the brain works than we did 25 years ago, but we still have so much to learn. Since I started working with living human tissue,
I have even more questions.”

He and his colleagues are elated that the Human Brain Lab increases the odds as never before that those questions will ultimately be answered.

--Christine Hurley Deriso