At the Lieber Institute for Brain Development in East Baltimore, dozens of brains from people who were diagnosed with post-traumatic stress disorder during their lifetimes are stored away in industrial-sized freezers intended to preserve vital tissue. The nonprofit research institute has amassed 81 of these PTSD brains—only a small portion of its nearly 2,000 total brains—in the six years it’s been open. It’s the biggest collection of post-mortem brains with a known diagnosis of PTSD.
Scientists at Lieber are researching schizophrenia and related brain disorders and have an ambitious plan for the PTSD collection. They want to pinpoint the genetic variants that raise a person’s risk for developing PTSD after trauma and find targets in the brain to treat the disorder more effectively with drugs.
Currently, people with PTSD are treated with a combination of talk therapy, or psychotherapy, and medications like antidepressants designed to treat symptoms of the disorder. About eight million adults in the U.S. have PTSD during a given year, according to estimates from the U.S. Department of Veterans Affairs. Globally, that number is much higher and includes not just combat soldiers but refugees, civilians exposed to war, and victims of domestic violence, assault, and sex trafficking.
Studying post-mortem brains is essential to PTSD research, says Joel Kleinman, associate director of clinical sciences at Lieber. Much of what scientists and medical professionals know about PTSD has been gleaned from observing symptoms of the disorder. What’s unknown are the molecular and cellular changes that occur in the brains of people who develop PTSD. Kleinman says these changes are “distinctly human” and cannot be studied in animals.
Kleinman and his colleagues will use RNA sequencing on the brains they’ve acquired to identify these changes. While the information in DNA is stable and dictates our biological traits, RNA helps carry out various tasks in cells, such as controlling gene expression. Gene expression, which can be measured with RNA sequencing, is important to researchers because the same gene may act in different ways under different circumstances.
RNA tends to degrade in post-mortem tissue, so scientists at Lieber acquire the brains within hours of the donor dying and rush them back to the lab to chill on ice. This helps preserve the integrity of the tissue so that the RNA can be properly analyzed later. Andrew Jaffe, a researcher at Lieber, has also developed an algorithm that measures the degree of post-mortem RNA degradation to help his colleagues determine how much RNA is able to be analyzed in the brains.
Lieber scientists have already done RNA sequencing on schizophrenia brains and published findings earlier this year about the discovery of a new protein linked to schizophrenia and related disorders, including depression, bipolar disorder, and attention deficit hyperactivity disorder. Researchers believe such proteins could be drug targets for these disorders.
Once all the brains have been sequenced, they will cross-reference genetic variants found by other researchers to be associated with PTSD with their data to look for connections. The researchers will also do this with control brains to compare the results.
Kleinman says he hopes the RNA sequencing will reveal the changes that need to happen to these genetic variants to cause the classic symptoms of PTSD. Kleinman and his team believe these brain changes, which involve proteins known as transcription factors, represent the holy grail for PTSD research: targets in the brain that could respond to drugs.
But RNA sequencing alone will likely not be enough to lead to drug discovery.
“The difficulty in RNA sequencing of post-mortem brains is determining whether the differences in expressions caused the PTSD, were the outcome of PTSD, or are the result or cause of something else entirely,” says Karestan Koenen, professor of psychiatric epidemiology at the Harvard T.H. Chan School of Public Health.
Koenen leads the PTSD working group within Psychiatric Genomics Consortium, an international collaboration of researchers, which is analyzing about 20,000 genetic samples from PTSD patients. In 2014, the consortium published data showing that more than 100 genetic variants are associated with schizophrenia risk. The consortium will do the same for its PTSD data within the next few years. That data will help scientists at Lieber narrow down which genetic variants it will focus on.
While she says PTSD research is in a period of “accelerated discovery,” she acknowledges the long road ahead before a drug for this devastating disorder is found. “There’s a tension between the need and how quickly we can move,” she says. “But the caution is that we want to make sure we have solid results that can inform drug discovery.”
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