Dr. Mirjana Maletic-Savatic was awarded her M.D. degree by the University of Belgrade, Serbia in 1985. She subsequently became Clinical Instructor in Medicine. In 1988 she received her M.Sci degree and was promoted to Assistant Professor of Biochemistry. Her work on the pathophysiology of cerebral ischemia resulted in his first peer-reviewed publication in 1989. Thus early in her career did she manifest interest in understanding the mechanisms and consequences of brain injury. An additional paper would appear in 1993 concerning work that she had participated in Belgrade characterizing the kinetics of an erythrocyte Na,KATPase that represented a potential indicator of extent of injury of that such a membrane-bound kinase within the central nervous system might experience under conditions of hypoxia or ischemia. Completing a year of residency in clinical biochemistry at Belgrade in 1991, she moved to Stony Brook University to pursue further training as well as clinical and research opportunities.
Dr. Maletic-Savatic spent nine months as Postdoctoral Research Associate under the supervision of stroke neurologist and biochemist, George C. Newman, at Stony Brook. These were followed by two years as Medical Research Scientist under the supervision of two distinguished senior scientists, developmental biologist/child neurologist, Nick Lenn and ion channel biochemist, J.S. Trimmer. Her work during these years resulted in her appearance in 1995 as first author of the important work she had undertaken with Lenn and Trimmer. The importance of this study of the spatiotemporal expression of rat hippocampal neuron K+ channel polypeptides is convincingly attested by the fact that it has to date been cited more than 123 times – an achievement of less than 1% of scientific publications. In November of 1994 Dr. Maletic-Savatic entered a two-year Postdoctoral Fellowship at the Cold Spring Harbor Laboratory under the direction of the distinguished developmental neurobiologists, Roberto Malinow and Kathy Svoboda. Her successful career as investigator had in the meantime qualified her for a Ph.D. in Neurobiology, which was awarded by the University of Belgrade in 1996.
Her work with Dr. Malinow would result in first authorship of two papers published in 1998; one reports on the regulation of calcium- evoked exocytosis in trans-golgi cell dendritic organelles of cultured rat CA1 hippocampal neurons, a paper that has been cited more than 61 times. The second demonstrates that this effect is mediated by calcium/calmodulin- dependent protein kinase II. It has been cited 39 times. Dr. Maletic-Savatic’s work with Drs. Malinow and Svoboda resulted in 1999 in publication in Science of a description of the rapidity with which dendritic morphogenesis may be induced in these CA1 cells. This classic paper has been cited more than 368 times and was recognized by Science as “Runner-up” for the “Breakthrough Publication of the Year.” She coauthored an additional methodological paper in 1999 describing an ingenious technique for two-photon imaging of living brain slices. It has subsequently been cited 35 times.
Dr. Maletic-Savatic served from 1998 to 1999 Clinical Instructor in Pediatrics at Stony Brook University and from 1999 and 2002 as Clinical Instructor in Child Neurology. In 2002 she also completed her own residency training in child neurology under the Direction of Mary Andriola, whereupon she was appointed to her current position as Assistant Professor of Neurology at Stony Brook. With Dr. Andriola and others she reported electroencephalographic studies of children with developmental dysphasia.
In 2001 Dr. Maletic-Savatic was named Visiting Scientist at Cold Spring Harbor. In 2002 she received a Career Development Award by the NINDS and in the same year was named one of four Outstanding Junior Member of the Child Neurology Society. In 2004 Dr. Maletic-Savatic became Director for Biological Research at the Cody Center for Autism at Stony Brook. In 2004 she received a Physician Scientist Training Award from the United States Army.
In February of 2005 she was promoted to Adjunct Assistant Professor at Cold Spring Harbor. In June of 2005 she was named Assistant Professor of Pharmacology and in June of 2006, Assistant Professor of Genetics, both at Stony Brook. In 2006 she also received the American Society for Clinical Investigation Travel Award. She has vigorously embraced opportunities for both basic and clinical research. She has participated with seven collaborators in further investigating the neural potential of stem cells derived from hair follicles, the results of which are currently in submission. In 2005 she published an intriguing study of the use of stem cells for the treatment of CNS demyelinating illnesses. Dr. Maletic-Savatic has directed studies for the generation and characterization of a monoclonal antibody against neural stem/progenitor (NSC/NPC) cells that will prove useful in the identification of these cells in experimental conditions.
Dr. Maletic-Savatic’s interest in brain injury and ensuing mental and motor handicaps in combination with her sophisticated understanding of stem cells led her to seek a method of combining these interests. She reasoned that it would be important to see whether prenatal stress resulted in diminished quantities of NSC/NPC in areas of importance for subsequent cognitive development. She chose the dentate gyrus for the very good reasons that 1) it is part of the hippocampus which plays a major role in memory and earning; 2) the subgranular zone of the dentate is the site of a robust population of NSC/NPC from very early stages of prenatal brain development, and 3) this is a region quite often implicated in the damage that may occur in infants subjected to premature birth or other forms of prenatal and perinatal stress. Her desire to study these phenomena in human infants presented her with the problem of devising a method that could safely identify and quantify the representation of NSC/NPC in distinction to neural and other cell lines at other levels of differentiation within the dentate gyrus. Remarkably, she solved this problem by novel adaptation of 1H-MR spectroscopy that entailed development of a signal processing method relying on singular value decompensation analysis.
The results have been, to say the least, stunning. She was able to demonstrate with in vitro methods of isolation of various cell lines a unique peak that represents a biometabolomic marker for NSC/NPC. She and her colleagues further demonstrated that during development and maturation of neural cells derived from NSC/NPC, this peak declined, while the well characterized peaks marking the appearance of neurons (NAA) and glia (Cho) increased. She has further demonstrated that this technique identifies the NSC/NPC peak in rat cortex after these cells have been transplanted. Finally, she has demonstrated that the technique works in human brain in voxels interrogating cortex and hippocampus. All of this work, recently submitted for publication, was presented this year at the AAN. The creativity and importance of the work of Dr. Maletic-Savatic was recognized as among the Top 5% Scientific Presentations for the year.
Dr. Maletic-Savatic’s Young Investigator proposal is aimed at employing this noninvasive technique to compare expression of NSC/NPC in hippocampal voxels of cadres of very premature, premature, and full-term infants. Success with this work may well provide a sensitive and important marker for early brain injury. More than that, it may provide a marker for the ensuing course of healing or efficacy of interventions that may be compared to clinical observations with growth and development. She is planning in particular to compare cadres of 2 -10-year-old children with cerebral palsies segregated into those with or without mental retardation to demonstrate whether or not her marker is specific for cognitive development. She will be able to compare her results with the white matter imaging biomarkers for poor development identified this year by a prior CNS Young Investigator, Terri Inder.
The success of Dr. Maletic-Savatic’s methods may well open up an entire field of research that may differentiate changes observed in children with mental retardation as compared to those with other disorders, such as autism. Already, the indefatigable Dr. Miletic-Savatic has completed a study of cerebral lateralization of children with disorders in the autistic spectrum employing the combination of a dichotic listening paradigm and fMRI imaging of activation. The method may permit her as well to explain something else that is of great interest to her: understanding why there is variation in extent and nature of long-term disabilities experienced by children who have been subjected to premature birth or other forms of stress.
Dr. Maletic-Savatic serves on numerous committees at Stony Brook in addition to Chairing the Research Planning Committee for the Cody Center for Autism. These include the Curriculum Committee of the School of Medicine; the Selection Committee for MD, PhD students; the Stem Cell Initiative Committee; and the Dean’s Leadership Advisory Council. She is a member of the mMRI Committee for Translational Research of the Brookhaven National Laboratory.