Stanley Center for Psychiatric Research

The Stanley Center for Psychiatric Research (SC) was created by a grant from the Stanley Medical Research Institute (SMRI) to the Broad Institute in February 2007, for 10 years. In May 2011, this grant was extended 5 years, to 2022.

The mission of the Stanley Center for Psychiatric Research is to discover the human genes that confer risk for bipolar disorder and schizophrenia and to use this information to develop new diagnostic tests and treatments for these illnesses. The center has extensive collaborations with investigators in the USA and Europe, maintaining close ties with Massachusetts General Hospital, McLean Hospital, and the MIT neuroscience community (Department of Brain and Cognitive Sciences, the McGovern Institute for Brain Research, and the Picower Institute for Learning and Memory).

The Stanley Center for Psychiatric Research is organized administratively as 6 main disciplines, each with a Director. These are typically listed in the order of their engagement in the overall drug discovery process:
Genetics (Steve McCarroll, Director)
Chemical Neurobiology (Steve Haggarty, Director)
Neurobiology (Li-Huei Tsai, Director)
Behavioral Neurogenetics (Tracey Petryshen, Director)
Medicinal Chemistry (Ed Holson, Director)
Clinical Applications (Roy Perlis, Director)

However, the core functional units of the Stanley Center are our cross-discipline Project Teams. Each Project Team focuses on all relevant aspects of each key research topic:

Genetics (Steve McCarroll, Leader) -- Focuses on identifying rare and common variants of human genes that confer risk for schizophrenia (SCZ) and bipolar disorder (BPD). Includes large-scale association studies and various sequencing studies (whole exome; targeted high-risk loci); cross-disorder studies (e.g., the Psychiatric GWAS Consortium, PGC); extensive international collaborations (International Schizophrenia Consortium, ISC and International Cohort Collection for Bipolar Disorder, ICCBD); and collaborations aimed at collecting >20,000 cases of each illness and a comparable number of controls. This team was led by Pamela Sklar until 1/31/11, when Dr. Sklar moved to Mt. Sinai School of Medicine. to be Chief of a new Division of Psychiatric Genomics

Emerging Genes (Jon Madison, Leader) -- Focuses on understanding the biological effects of the identified genetic variations. Encompasses approaches in Drosophila, zebrafish, mice and humans; and principles such as alternative splicing, microRNA regulation, ion channel function and gene expression; and technologies such as induced pluripotent stem cells (iPS), small molecule screens, RNAi knockouts, and construction of mouse models.

Wnt Pathway (Li-Huei Tsai and Jen Pan, Co-Leaders) -- The merger (as of fall 2010) of the previous ‘DISC1’ and ‘Lithium’ Project Teams, both initiated before any definitive results had come from the genetics analyses: DISC1 because of its clear role in psychiatric disease in at least 1 extended pedigree; and ‘Lithium--its mechanism of action and search for mimetics’ because of its 50+year history as the first-line treatment for BPD. Work by the Stanley Center and others (including new genetics results) has revealed that the underlying biology is really the Wnt signaling pathway. Thus this project focuses on multiple proteins involved in the pathway including DISC1, GSK3β, Akt, Dixdc1, and BCL9.

HDACs (Dan Fass, Leader) -- Focuses on identification, creation of, and in vitro and in vivo assays for selective HDAC2 inhibitors, based on the observation that specific HDAC2 inhibition improves learning and memory (Nature (2009) 459:55—Tsai lab and Stanley Center publication). A bona fide drug discovery program. Team may eventually expand to ‘Epigenetic Targets’, given prevalence of epigenetic regulators identified as risk loci in the genetic studies (for ex., other HDACs and histone modifying enzymes).

Clinical Applications (Roy Perlis, Leader) -- Established in spring 2010 to focus on several key developing issues and potential for clinical applications, including 1) planning the best clinical trial design(s) for cognition for the SC HDAC2 inhibitor (from the HDAC Team); 2) potential therapeutic value of certain drug combinations (based on the Chem Bio group’s results of a screen for Wnt signaling; 3) potential diagnostic applications (from pharmacogenomics, Wnt signaling in cases vs. controls, gene expression signatures, PET ligands).

One goal, as well as a constant challenge, is to be sufficiently nimble to respond to new opportunities and data—to shift resources and priorities as needed to stay focused on the mission of the Stanley Center. Examples of this over the last few years are our decisions to end the ‘Neurotrophic Factors’ team (which had been focused on neuregulin) and to create an ‘Emerging Genes’ Team to focus on the functional biology of specific genes (such as ANK3, CACNA1C, NRGN and CPG2) identified by the Genetics analysis. This Emerging Genes team also encompassed formation of an iPS group at MGH (also led by Jon Madison), to learn, develop and apply the new iPS technology to psychiatric disease research.