Jefferson Investigates: Transcription in Mitochondria, Primary Care & Opioid Use Disorder, Stigma & Traumatic Brain Injury

The U.S. is in the midst of an opioid epidemic; overdose deaths from synthetic opioids such as fentanyl have increased more than 100-fold since 1999. Medications like buprenorphine, methadone and naltrexone can all help treat opioid use disorder (OUD), curbing relapse, overdoses and death. But many barriers exist to people with OUD getting these medications, from providers not receiving adequate training to people with OUD feeling too stigmatized to find a specialist.

“All these little things can be major barriers when you're in the throes of withdrawal or addiction,” explains psychologist Erin Kelly, PhD.

Along with a team led by Dr. Kelly, Gregory Jaffe, MD, started a substance use disorders clinic embedded within the Jefferson family medicine clinic and residency program aiming to break some of those barriers and expand access to life-saving medication within primary care. They published their findings in Substance Use & Misuse.

"The goal of this was to help create low-barrier access to these medications,” Dr. Kelly says. Primary care providers (PCPs) are often the first point of contact for a patient in the medical system, making them a key route for prescribing OUD medications.

Initially, PCPs in the practice were trained to become X-Waiver certified — a certification that was required up until 2022 to prescribe certain OUD medications. The physicians also completed training on topics including harm reduction and trauma-informed care. The largest increase in medication for OUD within the practice came after the implementation of the substance use disorders clinic.

Patient feedback was overwhelmingly positive: They appreciated how effective and easy the treatments were to access, noting that they didn’t feel stigmatized by their PCPs.

Dr. Jaffe says programs like these can expand and position PCPs at the front lines of combating the opioid epidemic. Sidney Kimmel Medical College students Sarah Lawson, Allie Hamilton, Jordan Lazarus and postdoctoral researcher Erica Li, PhD, helped conduct the study.

“We need primary care providers to be equipped to properly address substance use, both screening and treatment,” Dr. Jaffe says.

By Marilyn Perkins

Aging, neurological diseases and our bodies’ stress response are all linked to the tiny power plants inside each cell known as mitochondria. To function properly, mitochondria must first read instructions from their DNA and then copy it over into mRNA in a process called transcription. Now, researchers at Thomas Jefferson University have reconstructed transcription in human mitochondria in unprecedented detail. The findings, published in Molecular Cell, show how the molecular machinery works and reveal potential drug targets for mitochondrial diseases.

“When we understand this key process, we can validate targets for a new class of drugs that restore mitochondrial potential,” says structural biologist and senior author Dmitry Temiakov, PhD.

Dr. Temiakov, a member of Sidney Kimmel Medical College, and his lab were the first to determine the structure of a key enzyme, known as human mitochondrial RNA polymerase, in 2011. Since then, he and his team have worked to understand the enzyme’s “molecular gymnastics.” It changes shape and interacts with other proteins in the cell as it begins its job of transcription. In this latest study, the researchers used high-powered microscopes and advanced computational methods to visually capture the enzyme and its helper proteins.

The team reconstituted the process of transcription in a test tube, flash froze samples on microscopic grids and painstakingly imaged them from multiple angles with an electron microscope. This method, known as cryo-EM, can reveal a protein’s 3D structures in near-atomic detail.

Karl Herbine, a graduate student who led the project (presently a postdoctoral fellow at University of Pennsylvania), assessed more than 1 million images over the course of three years. The fruits of his perseverance is a molecular movie that shows just how the enzyme recognizes the correct starting point on DNA, brings in helper proteins, begins to copy the genetic code into mRNA, and finally transitions into a fully active and stable mode.

With one in 5,000 people affected by mitochondrial disease, the findings open the door to discovering drugs designed to restore mitochondrial health.

“When we see how this fundamental process works,” says Dr. Temiakov, “we can begin to fix what’s broken.”

By Roni Dengler

More than 5 million Americans are living with permanent TBI-related disability related to traumatic brain injury,  which can severely impact quality of life. Unfortunately, people with TBI are often socially stigmatized because of their disability. This public stigma may cause people with TBI to believe they are somehow inferior or less worthy than people without disabilities, a phenomenon known as internalized stigma. Umesh Venkatesan, PhD, a researcher at Jefferson Moss Rehabilitation Research Institute, and collaborators wanted to examine the extent to which discrimination, a type of public stigma, is internalized by people living with TBI. The study assessed the potential consequences of internalized stigma on their health and behavior.

In their recent study, Dr. Venkatesan and his colleagues administered questionnaires assessing perceived discrimination and internalized stigma to 84 adults with TBI. Their data suggest that there are different levels of stigma internalization, in that some people with TBI may be more likely than others with TBI to think and feel negatively about themselves when encountering discrimination due to their disability. Additionally, the researchers found evidence of a “why try” attitude, where people with TBI who experience high levels of internalized disability stigma may not even attempt certain tasks or engage in social activities because of a fear of failure. This process could have major health implications for people with TBI, increasingly isolating and alienating them from general society.

Although this study did not test any solutions to public or internalized disability stigma, it highlights a problem that significantly impacts the lives of people with TBI and should be addressed.

“Continued work on internalized stigma ultimately will allow us to develop interventions to help people cope with public stigma and cultivate more adaptive beliefs about themselves. Education and empowerment are critical,” says Dr. Venkatesan. He also suggests that support groups and other types of peer support networks may help those with TBI to feel a sense of community belonging and safety, buffering against harmful effects of public stigma like stigma internalization.

By Moriah Cunningham