Dr. Shani Stern is an assistant professor in the Sagol Department of Neurobiology at the University of Haifa. Her lab focuses on human brain diseases and disorders, specifically bipolar disorder, Parkinson’s disease, and rare mutations that cause intellectual disability, epilepsy and autism. Dr. Stern uses molecular biology combined with biophysical, electrophysiological, and numerical simulation to facilitate the use of induced pluripotent stem cell (iPSC) technologies. This is where adult cells from human patients are reprogrammed into pluripotent stem cells. From these pluripotent stem cells the Stern lab then differentiates neurons and other brain cells. The derived human neurons have the same genetics as the patients and serve as an excellent model for studying these disorders. Dr. Stern hopes that understanding the underlying mechanisms will lead to developing precision medical protocols and identifying biomarkers for better diagnosis and improved prognosis.
Dr. Stern began her career at Intel and Motorola after graduating from Tel Aviv University with a degree in electrical engineering. She developed speech and MODEM algorithms and received the Motorola CEO award for research and development. She filed several successful patents as the lead inventor for improvements in speech algorithms. Dr. Stern returned to academia and completed her PhD at the Weizmann Institute, combining physics with neurobiology and researching neuronal networks and excitability in health and disease. She did her postdoctoral research at the Salk Institute in San Diego in the lab of the Institute’s president, where she shed light on the cellular mechanisms underlying psychiatric disease.
Please describe your current research, the focus of your lab, and the practical implications of your research
Our lab uses patient-derived neurons and different cell types – blood samples and skin samples – from individuals with neurological disorders, specifically bipolar disorder, Parkinson’s disease, and rare mutations that cause intellectual disability, epilepsy and autism. We take adult cells and reprogram them back into a stem cell state. We then differentiate these stem cells into brain cells and study them using electrophysiology (whole cell patch clamp), molecular assays, and computational modeling. The neurons are genetically identical to the neurons in the patient’s brain and provide more accurate models than animal models. We use these methods to investigate mechanisms of autism and intellectual disabilities in rare mutations in several genes.
My focus started with Parkinson’s and bipolar disorder, but I received more inquiries for autism from parents with affected children and I wanted to help find better treatment by investigating the mechanisms that are involved, then targeting them with specific drugs.
Fifteen percent of Parkinson’s patients have a genetic mutation while the other 85% are “sporadic.” In those sporadic cases, no genetic component was found so far. Therefore, animal models cannot recapitulate the changes that occur in the patient. The advent of human derived neurons is that we do not need to understand what the genetic changes are because the derived neurons have the same DNA as the patient and are therefore a precise model even when we cannot track down the changes in the patients’ DNA. Using RNA sequencing and electrophysiology we found shared altered pathways in the patients’ dopaminergic neurons both when there are specific mutations as well as in the sporadic cases.
Our research with bipolar disorder has enabled us to find that hippocampal neurons from bipolar disorder patients are hyperexcitable. Moreover, the patient derived neurons were physiologically unstable and shifted their excitability state easily. We were also able to identify changes between the patients that respond well to lithium treatment and those that do not respond. Using machine learning algorithms, we were able to predict with a very low error rate if a patient would respond to treatment or not and we are currently working on simplifying the prediction scheme to make it useable in the clinic.
What do you enjoy most about your research?
I was always intrigued by the complexity of the brain. I have a personal reason for wanting to study these disorders. I have a brother with autism spectrum disorder and an intellectual disability. Many parents of children with similar disorders approached me when I came back from my postdoctoral training and asked me to help them. Some of these parents are now volunteers in the lab working with their own children’s cells seeking mechanisms and possible treatment. We recently were able to observe how neurons that were derived from a child with a mutation that causes severe epilepsy and autism were hyperexcitable, and the neuronal network as an assembly had less inhibition. The hyperexcitability stemmed from changes in the neurons’ potassium currents and these are now targets for possible treatment.
What does it mean to you to be part of the Zuckerman Faculty Scholars Program?
The network of Zuckerman scholars is very supportive. I have met many people with whom I would like to collaborate. The funding enabled me build a large lab with state-of-the-art equipment. Many parents of children with autism approach me to work with them and I hope to conduct more research into autism so I can help them. My lab also has exciting results in the field of Parkinson’s disease, and we are using information theory to gain new perspectives on mechanisms of different drugs such as lithium in bipolar disorder.
Where do you hope your research will have the greatest impact?
My goal is to discover treatments to help people who suffer from Parkinson’s and autism as well other neurological disorders. In the future we hope to use gene therapy as well as being able to inject reprogrammed cells to help these conditions improve.