About noon most days, the Lieber Institute for Brain Development in East Baltimore gets a case — that is, a brain. Almost immediately, neuropathologist Rahul Bharadwaj gets to work, inspecting it for any abnormalities, such as tumors or lesions.
Often, the brains come from the Medical Examiner’s Office, just a 15-minute drive across town. On other days, they are flown in — packed on dry ice — from around the country.
Since opening in 2011, the institute has amassed more than 3,000 of these post-mortem brains that they are studying to better understand the biological mechanisms behind such neuropsychiatric disorders as schizophrenia, major depression, substance abuse, bipolar disorder and post-traumatic stress disorder. About 100 brain banks exist across the country. But Lieber, founded with the support and funding of a wealthy couple whose daughter suffered a psychotic break in her 20s, is the biggest collection dedicated specifically to mental conditions.
Current therapies for neuropsychiatric disorders — antipsychotics and antidepressants — treat symptoms rather than the underlying cause of illness, which remains largely unknown. And while they can be lifesaving for certain people, they can cause unpleasant and sometimes serious side effects. In some cases, they won’t work at all.
Most of these drugs were also discovered by accident. Lieber’s goal is to unravel what happens biologically in the brain to make these conditions occur and then to develop therapies to treat these conditions at their root cause, or even prevent them from happening. “Most of us have some of the variations in the human genome that are associated with psychiatric problems,” said Daniel Weinberger, director and chief executive of the institute.
More than 100 genetic variants have been identified as possibly related to schizophrenia, and about 30 variants have been linked to bipolar disorder. What’s not known is how having one of these genetic variants or a group of them alters the structure and function of the brain — and why some people who harbor these variants don’t develop mental illness while others do.
Researchers think a combination of genetic, lifestyle and environmental risk factors changes the brain’s chemistry in people with neuropsychiatric disorders, causing imbalances in neurotransmitters, chemicals that send messages to nerve cells in the brain.
“Once we understand some of these genetic risk mechanisms, then we can start thinking about what molecular pathways seem to be perturbed,” said Thomas Hyde, Lieber’s chief medical officer. “The key is to find new therapeutics and then figure out which is the best target population for those therapeutics to work in.”
Lieber researchers first do a physical examination of the brains. DNA, RNA and proteins are extracted and analyzed to identify genetic mutations and observe how genes are expressed in different cells. Using a technique called laser capture microdissection, they can isolate specific brain cells from a mixed population.
Through their research, the institute has identified a handful of promising drug candidates, including one for traumatic brain injury and another for a rare form of autism, a neurodevelopmental disorder.
Most of the Lieber Institute’s brains come from people who have died unexpectedly.
The morning hours leading up to a case are a flurry of activity. The institute gets a call from one of four medical examiner’s offices.
At that point, it’s Hyde’s job to contact next of kin and ask permission to use their loved one’s brain for research. He has a small window of time in which to get that consent — one to three hours. Often, he’s successful. More than 60 percent of family members asked agree to brain donation.
“To me, it’s remarkable that, given the sudden loss of a loved one, people are so generous with the tissue donations,” he said.
Once a brain arrives, it is ushered into a small, well-lit room. After examining a brain, Bharadwaj cuts it into slices, to expose certain parts — such as the amygdala, the mass of neurons located deep in each hemisphere that serves as emotion-processing centers. Abnormal functioning of the amygdala has been found in some patients with depression, PTSD and phobias.
The slices are photographed, numbered, put on dry ice and stored in industrial-sized freezers set at minus-80 degrees.
The blood that’s collected, along with brain tissue, is used for DNA sequencing — a process in which researchers determine the full readout of a person’s genetic code. It was once thought that a person has the same DNA throughout their body. But researchers have found that certain genetic changes — deletions and duplications of DNA — may appear only in neurons in the brain.
Michael McConnell, assistant professor of biochemistry and molecular genetics at the University of Virginia, is investigating what role these deletions and duplications of DNA, called copy number variants, play in neuropsychiatric disease. He has been studying brains in the Lieber collection, pulling out single cells from brain tissue and profiling their DNA.
He thinks these variants might raise the risk of neuropsychiatric disease. And because brain cells stick around in the body longer than other cells, these variants could be with people for most of their lives.
This is where brains prove invaluable. Most genetic studies of neuropsychiatric disorders have looked at only blood, not brain cells. “Maybe if we look at the brain we’ll find that they’re not as rare as we think they are,” he said. If a certain variant is in a big enough chunk of the population, “it’s worth making a drug to try.”