How Brain Gene Expression Changes Between Life and Death

Since the publication of the Human Genome Project, researchers have expanded the field of genomics to probe deeper into the underpinnings of human biology and disease, including studies of the body’s transcriptional and protein profiles. These technologies, collectively referred to as multiomics or just omics, have provided insights into human health and disorders.

In the field of neuroscience, though, omics research has largely relied upon postmortem samples to draw conclusions about the molecular functions of the brain. Questioning whether this accurately reflected the human brain of a living person, two researchers at the Icahn School of Medicine at Mount Sinai, psychiatrist and geneticist Alexander Charney and neurosurgeon Brian Kopell, teamed up to put the belief to the test. Together, the two started the Living Brain Project to study the biology of the human brain during life.

A Surgical Solution to Living Tissue Trouble

As a psychiatry resident in 2012, Charney was studying the genetic factors of schizophrenia as omics began to take shape in the psychiatry field. However, he said, “I was struck by how the field was kind of completely mobilizing around the use of postmortem brain samples to understand the biology of mental illness.”

Since these findings would serve as the basis for psychiatric drug development, he was concerned about how these potential differences between living and deceased brains could affect the translation of their results. Obtaining living brain tissue is complicated, though, leading to researchers’ reliance on postmortem samples.

As a psychiatrist, Charney considered studying brain tissue from patients who underwent deep brain stimulation (DBS) and whether he could collect living brain tissue from surgical instruments. He reached out to Kopell who performed DBS surgeries. “This just resonated with my mission as an academic neurosurgeon,” Kopell said.

The team’s initial attempts to use residual cells on Kopell’s devices failed, but Kopell suggested an alternative: During DBS surgery, he cauterizes the tissue where he will insert the probe, so he could take a biopsy of that region beforehand with no impact on the patient.¹

“Because neurosurgeons and psychiatrists [and] scientists aren't just sharing ideas regularly, something that would seem impossible to scientists—the notion that a brain sample from the prefrontal cortex could be obtained for research—to a neurosurgeon is not; this isn't impossible at all,” Charney said.

Kopell agreed, “The great projects are where different disciplines come together and harness their unique sort of perspectives together.”

After overcoming the hurdle of collecting living brain samples, Charney explained that the team turned to designing as rigorous a study as possible, “or no one would believe the findings,” he said.

The most common region of the brain targeted in DBS is the prefrontal cortex, which coincides with the bulk of studied postmortem brain samples, allowing the team to compare the same brain region. The researchers also attempted to match for neurological conditions, age, sex, and other characteristics in their tissue criteria. Lastly, “The sample size needed to be big,” Charney said. “We wouldn't just need samples from a handful of patients. We would need to obtain biopsies from hundreds of people.”

The Living Brain Project Brings Neuroscience to Life

In their first study, the team described huge differences in the gene expression between living and postmortem brain tissue.² “Which is not surprising given a dead person can't do anything, and a living person can do so many amazing things,” Charney said. The team subsequently explored these differences further, looking at differences in RNA processing, protein expression, and cell types using omics tools.^3,4

“There's all different kinds of things you can ask in the context of studying living people that just isn't possible with postmortem samples,” Charney said. “Our goal is to understand how the brain works, develop new treatments for severe illnesses. So, we want to use the Living Brain Project as a platform to do that.”

For example, one advantage of studying the living brain with the team’s DBS procedure is the ability to collect data from electrical signals across the sample area while an individual is completing a task and then compare those results with gene expression.⁵ Using other methods, Kopell explained, researchers had to study such brain function separately. “One of the things that I'm most excited about where we're going to take this is this intersection of disparate signals, if you will, from a living brain into a coherent whole,” Kopell said.

Additionally, Kopell said, “This is an opportunity to not just answer the questions that both Alex and I are interested in, but to provide a unique set of data that will be enduring in its utility for science, for scientists in years to come.” For example, brain implants have been developed that can treat a variety of neurological and psychiatric conditions.⁶ Kopell said that more of these will increasingly begin to use artificial intelligence, which requires the algorithms be trained on relevant information. “Could you imagine what a data set like this could do to potentially train these devices?” Kopell asked.

Although the researchers answered their initial question in the Living Brain Project, Charney said, “We're just beginning to scratch the surface of what can be learned from this approach.”