Rakesh Karmacharya

Associate Professor of Psychiatry
Harvard Medical School
Psychiatric and Neurodevelopmental Genetics Unit

Center for Human Genetic Research
Massachusetts General Hospital
Richard B. Simches Research Center
185 Cambridge Street
Boston, MA 02114
Phone: 617-726-5119
Email: karmacharya@chgr.mgh.harvard.edu

Dr. Karmacharya is a physician scientist who is investigating the cellular and molecular underpinnings of schizophrenia and bipolar disorder. He received his AB in biochemistry from Harvard University, MS in molecular biophysics and biochemistry from Yale University and his MD and PhD in biophysics from Albert Einstein College of Medicine. His graduate studies focused on theoretical studies of the quantum mechanics of proton tunneling in condensed phase, under the mentorship of Professor Steven D. Schwartz.

He did an internship in internal medicine at Mass General, followed by a residency in psychiatry in the Mass General-McLean program, where he served as the Chief Resident of the Schizophrenia and Bipolar Disorder Program. After his residency, he undertook postdoctoral studies in the Chemical Biology Program at the Broad Institute of Harvard and MIT, under the mentorship of Professor Stuart L. Schreiber.

He is currently the director of Stem Cell Research in the Center for Experimental Drugs & Diagnostics at Mass General, medical director of the OnTrack Program for First-Episode Psychosis at McLean Hospital and an associate member in the Chemical Biology Program at the Broad Institute of Harvard and MIT. His current research aims to discover new pathways relevant to disease biology and develop small molecules that can be translated into novel therapies through the application of chemical biology approaches.

Projects:

Research in the Karmacharya Laboratory uses approaches at the intersection of chemical biology and stem cell biology in order to investigate cellular pathways relevant to neuropsychiatric disorders.

A major project in the lab involves the identification of disease signatures for schizophrenia and bipolar disorder using patient-derived neurons generated from induced pluripotent stem cells (iPSCs). We differentiate iPSCs to cortical neurons and study differences in synaptic and dendritic spine biology in specific cortical neuron subtypes, using super-resolution microscopy as well as high-resolution calcium imaging studies. We undertake studies under basal conditions, as well as in the presence of perturbations with sets of annotated small molecules, in order to uncover disease-related vulnerabilities in specific cellular pathways. We couple these studies with phosphoproteomic, metabolomic and gene-expression studies to delineate the nature of cellular process that are aberrant in disease. We are also interested in developing new small-molecule potentiators of neuronal activity-dependent induction of Arc (Activity-regulated cytoskeleton-associated protein; Arg3.1) and investigate their effects on synaptic biology in human cortical neurons, in order to develop small molecules with pro-cognitive potential.

Another project in the laboratory includes the role that non-histone acetylation of beta-catenin and Akt plays in synaptogenesis. We use small molecule probes to dissect the mechanisms underlying the effect of histone deacetylase 6 (HDAC6) on synaptic stabilization.

Finally, we are interested in using small-molecule gene expression databases in order to identify compounds that have potential therapeutic potential. Along this line, we have identified a small molecule whose gene expression profile is strongly anticorrelated to the gene expression profile for Parkinson's Disease and we are undertaking studies in human iPSC-derived dopaminergic neurons to delineate the mechanistic underpinnings of neuroprotection in dopaminergic neurons.

Publications:

See a list of Dr. Karmacharya's publications

Staff:

Annie Kathuria , PhD, Postdoctoral Fellow
Annie received her PhD from King’s College London where she studied the role of SHANK3 in autism spectrum disorders using human iPSC lines, under the mentorship of Professor Jack Price and Professor Fiona Watt. Her current work involves the development of three-dimensional cellular disease models using organoids and cortical spheroids in order to study the disease biology of schizophrenia and bipolar disorder.

Shaunna S. Berkovitch, PhD, Postdoctoral fellow.
Shaunna received her BS in Chemistry from the Massachusetts Institute of Technology, followed by a a PhD in molecular and cellular biology from Harvard University. For her graduate studies, she investigated novel oligonucleotide inhibition strategies for human telomerase under the mentorship of Professor Gregory Verdine.

Bradley Watmuff, PhD, Postdoctoral Fellow
Bradley received his PhD in Stem Cell Biology from Monash University, where he worked on the functional development of mouse and human embryonic cell-derived midbrain dopaminergic neurons, under the mentorship of Professor John Haynes. His current work involves the development of methods for directed differentiation of human induced pluripotent stem cells into hippocampal CA3 neurons.

Bangyan Liu , MS, Research technician
Bangyan received his BS and MS in biochemistry from Brandeis University where he worked models of tau pathology in yeast under the mentorship of Professor Dagmar Ringe and Professor Gregory Petsko. He is undertaking studies aimed at studying cellular pathways involved in neuroprotection of human dopaminergic neurons in Parkinson’s Disease.

Lucius Xuan, Undergraduate student
Lucius in an undergraduate student who is using chemical biology and functional genetic approaches to understand the role of HDAC6 in synaptogenesis in human neurons.

Laboratory Alumni

Jonathan Iaconelli, BS, Research technician.
Jonathan received his BS in biology from the Emory University and worked in the laboratory on the underpinnings of HDAC6-mediated changes in acetylation of beta-catenin. He is currently a graduate student in Chemistry at Dartmouth College.

Steven Toffel, Harvard Stem Cell Institute (HSCI) intern
Steven worked on the development of methods to characterize and quantify dendritic spines in cortical neurons differentiated from human iPSCs. He is currently enrolled in an accelerated medical school program at the University of Florida.

Nivanthika Wilamasena, Undergraduate student.
Nivanthika was an undergraduate studnent at Harvard College majoring in chemical and physical biology. She undertook studies aimed at identifying and characterizing novel small molecules that had gene-expression profiles that were anti-correlated to the gene-expression profiles in Parkinson's Disease. She is currently a graduate student at Harvard University.

Berke Sengun, Harvard Stem Cell Institute (HSCI) intern
Berke worked on mechanisms related to HDAC6 effects on beta-catenin in human neural progenitor cells. He is currently a medical student at Koc University in Turkey.

Joanne Huang, BS, Research technician
Joanne received her BS in biology from the Massachusetts Institute of Technology (MIT).  She undertook metabolomic studies of patient-derived cells from subjects with schizophrenia and bipolar disorder. She is currently a medical student at University of Pittsburgh.

Julia Whitten, Undergraduate student
Julia was an undergraduate student and she undertook studies aimed at developing methods for the study of dendritic spines in human cortical neurons.

Sun Young Chung, Harvard Stem Cell Institute (HSCI) intern
Sunny worked on the effects of HDAC6 inhibitors on synaptogenesis in human iPSC-derived neurons. She is currently working in the Lorenz Studer laboratory at the Memorial Sloan Kettering Cancer Center.

Elizabeth G. J. O'Brien, AB, Research technician
Elizabeth received her AB in molecular and cellular biology from Harvard University. Her work involved the gene expression and image-based profiling of human cell to identify disease signatures for psychiatric disorder. She is currently a medical student at Yale University.

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