As a postdoctoral fellow working with neurogeneticist Huda Zoghbi at Baylor College of Medicine,Sameer Bajikar began to study a pair of neurodevelopmental disorders that work as two sides of the same coin, in a way. Rett syndrome and MECP2 duplication syndrome are both caused by mutations in a single gene: MECP2. This gene is known as a dosage-sensitive or “Goldilocks” gene because too much or too little of it results in two distinct disorders. Rett syndrome occurs when genetic changes make MECP2’s function or levels decrease abnormally, while MECP2 duplication syndrome makes the gene’s function or levels increase.
Both of these genetic disorders are rare and cause severe impairments in the young children diagnosed with them. Rett syndrome, which more commonly affects girls, is marked by symptoms such as mobility loss, a slowing of development and seizures. MECP2 duplication syndrome, which primarily affects boys, delays and regresses motor development, causes seizures, and is linked to recurrent, deadly respiratory infections.
Bajikar hopes to unlock the inner workings of MECP2, the Goldilocks gene behind both disorders. In January 2024, he will bring his work to UVA as an assistant professor in the Department of Cell Biology in the School of Medicine and the Department of Biomedical Engineering in the School of Engineering and Applied Science.
“Studying one gene across two different disorders can teach us similarities and differences in how these neurodevelopmental disorders arise,” Bajikar said. “Then, we can ask: What can we learn from those similarities and differences to devise therapeutics?”
Bajikar is a double Hoo, having earned his bachelor’s degree in biomedical engineering from the University of Virginia in 2010, followed by a Ph.D. in 2016. While at UVA, Bajikar conducted research under the mentorship of Kevin James, the John Marshall Money Professor of biomedical engineering. As a Ph.D. student, Bajikar combined experimental and computational tools to understand cell-to-cell variation in cancer.
He joined Dr. Huda Zoghbi’s research group at Baylor College of Medicine as a postdoctoral fellow in 2017 with the aim of pivoting to study a different problem.
Bajikar was drawn to Dr. Zoghbi’s groundbreaking study of rare genetic disorders like Rett syndrome and MECP2 duplication syndrome. There are gaps to fill in the field: researchers have studied the disorders for decades, but there are few treatments available and scientists don’t yet know exactly how abnormal MECP2 function or levels cause brain function to go awry.
“These disorders are severe and greatly affect many facets of the lives of the patients and their families,” Bajikar said. “Given the current limited treatment options, every advancement we make in the study of these disorders, even if small, could have significant impact for them.”
Bajikar has worked to sift through the subtle molecular changes taking place in the brain with the two disorders. There could be thousands of small changes at play, he explained. In a study published early this year, Bajikar and his peers identified an important interplay between the MECP2 gene and another gene known as growth differentiation factor 11, or Gdf11.
They found that Gdf11 expression decreases in Rett syndrome and increases in MECP2 duplication syndrome — changes mirroring those made to MECP2 with the two disorders. In a mouse model of MECP2 duplication syndrome, the team also found that genetically decreasing high levels of Gdf11 led to improvement of neurological abnormalities.
The research earned Bajikar an Independence Award from the International Rett Syndrome Foundation.
“This work paves the way in exploring Gdf11-based therapeutics for Rett syndrome and MECP2 duplication syndrome,” Bajikar said.
While finishing up his postdoctoral fellowship, Bajikar eyed UVA for the third time in his career. The University had grown in that time, he observed, furthering its commitment to neuroscience research with the launch of the UVA Brain Institute.
“I was drawn back to UVA because I had experienced the University’s collaborative and collegial environment of research firsthand,” Bajikar said. “The ability to interface with neuroscientists, pharmacologists, engineers — sometimes all within the same building — will enable us to form connections and develop innovative approaches for studying these severe disorders.”
As an assistant professor at UVA, Bajikar will focus next on developing new human neuronal modeling systems to study Goldilocks genes and syndromes globally. His team will use the models to look for common molecular and biological pathways disrupted across multiple neurodevelopmental disorders.
It’s about cutting through the noise of all that goes on in the brain to pick up key biological signals, Bajikar said. He will also continue to study Gdf11’s importance to brain development and the effects of disrupting Gdf11 signaling on brain function.
Bajikar looks forward to tapping into UVA’s collaborative spirit as a member of the Department of Cell Biology and the Department of Biomedical Engineering.
“I’m excited to connect with researchers in both schools,” Bajikar said. “Studying neurodevelopmental disorders in depth will require the collaboration of many, each with their own expertise and perspective.”