Schahram Akbarian, MD, PhD, is a recipient of the prestigious NIH Director’s Pioneer Award (DP1), a five-year award that supports creative scientists who are pursuing pioneering approaches to major scientific challenges.
Most clinical studies benefit from taking repeated measurements over weeks, months, years. Researchers studying epigenetic disease processes in the brain don’t have that luxury. “You harvest the brain, and you only get one time point,” says Schahram Akbarian, MD, PhD, Professor of Psychiatry and Neuroscience and Chief of the Division of Psychiatric Epigenomics at the Icahn School of Medicine at Mount Sinai. “In this field, most studies are cross-sectional.”
Now, Dr. Akbarian is developing a novel method — longitudinal epigenetic profiling — that allows him to study epigenetic changes in the brain over time. The innovative idea has earned him the National Institutes of Health (NIH) Director’s Pioneer Award (DP1), a five-year award that supports creative scientists who are pursuing pioneering approaches to major scientific challenges. The project, Single Chromatin Fiber Sequencing and Longitudinal Epigenomic Profiling in HIV+ Brain Cells Exposed to Narcotic and Stimulant, will use the new technique to explore dynamic changes in HIV-infected cells in the brain.
“In the last 10 or 15 years, research on the epigenetics of disease has taken off, thanks to modern sequencing technologies that allow us to study genome organization in a relatively cost-efficient way,” Dr. Akbarian says. “There’s a big need for more research on HIV in the brain, and I hope to morph this new idea into something specific and exciting for HIV research.”
HIV and the Brain
At the Akbarian Laboratory of Epigenetic Regulation of the Human Brain, much of the research has focused on psychiatric diseases such as schizophrenia and depression. Several years ago, Dr. Akbarian began to extend his research to HIV, in part because so many critical questions about the virus’ impact on the brain remain unanswered. More than 38 million people worldwide are living with HIV, and 1.5 million were newly infected in 2021, according to the World Health Organization. Some 75 percent of them have received antiretroviral therapy — yet for many, brain-related symptoms remain.
HIV can infect the microglia, the innate immune cells of the central nervous system, and can also cause inflammation. People with HIV can experience a range of symptoms, including headaches, forgetfulness, mood disorders, and behavioral changes. “People are still having neurological symptoms from HIV infection, even if they take antiretroviral drugs. The question is, why? What’s causing damage in the brain?” Dr. Akbarian says.
He hopes that his longitudinal epigenetic profiling method will begin to answer that question. The technique involves differentiating pluripotent human stem cells into microglia, then introducing those microglia into the brains of mice. Using epigenomic tagging of single chromatin fibers, he and his colleagues can explore dynamic changes of epigenomic dysregulation of the cells over time. “We can switch it on and off, then months later, isolate the immune cells and see how genome organization looked four months ago,” he says. “It’s a bit like a telescope that allows astronomers to look back in time in the universe. This “telescope” allows us to look back in time in the cell.”
In this study, he is focusing on HIV-infected cells that have also been exposed to opioids and stimulants. Drug abuse is a major risk factor for HIV, because drug use increases risky behaviors that can make a person more susceptible to infection. “A brain that’s exposed to drugs of abuse and to HIV is probably more unhealthy than brains from a person with HIV but no history of drug use,” Dr. Akbarian says. “We want to see if exposure to drugs of abuse makes the brains more vulnerable to infection with HIV, or to the neurological defects that HIV can trigger.”
A third goal of the project, he says, is to contribute to efforts to rid the body of HIV for good. HIV inserts itself into the genome, an ingenious trick that allows it to hide from the immune system and makes it devilishly complicated to treat. “The big question is, does HIV do this in the brain, and if so, how can we flush it out?” Dr. Akbarian says. “If we can rid the body of HIV in every cell, people can stop taking antiretroviral medication”— and effectively be cured of HIV.
Advancing Psychiatric Epigenetics Through Collaboration
The project is in its early stages, but if this longitudinal method proves effective, Dr. Akbarian hopes it could lead to new innovations for studying other diseases of the brain. Many psychiatric conditions, such as schizophrenia and depression, emerge in young adulthood. However, many researchers suspect the disease process begins much earlier, possibly even prenatally. “There’s lots of indirect evidence, but we can’t look back in time. If we study the brain of a person with schizophrenia, we have no idea what happened in their brain earlier in life,” he says. Someday, this novel longitudinal technique may uncover some important clues.
First, though, he’s applying the method to the intertwined problems of HIV and drug use. Though Dr. Akbarian’s name is on the Pioneer Award supporting the study, it’s a project he says he could not have done without support from his colleagues at Mount Sinai. “I’m a newcomer to the field of HIV. I wouldn’t be able to do this without the exceptionally collaborative atmosphere among my colleagues at Mount Sinai, including Benjamin Chen, MD, PhD, Talia Swartz, MD, PhD, and Susan Morgello, MD, who are doing experimental HIV research and were willing to help me learn,” he says. “It’s ironic that this award is in my name, because the success of this project depends so much on teamwork with these HIV researchers, as well as stem cell scientists including Samuele Marro, PhD.”
The collaborative culture at Mount Sinai makes this kind of innovation possible, he adds. “Mount Sinai has precisely the right mixture of top-notch basic neuroscience, top-notch clinical neuroscience, and a very active hospital setting,” he says. “Together they give very fertile soil to do productive research in the fields of neurology and psychiatry.”