The unique environment at Boston Children’s Hospital provides unprecedented opportunities for the development of new diagnostic tools and therapies. The center’s current services and facilities include a Human Neuron Core, Clinical Research Operations, Human Neurobehavioral Core Service, Research Participant Registry, Biomarkers Unit and Translational Genomic Medicine Unit, with many more services in development.
RSZ TNC members at Boston Children’s and their collaborators have access to a broad range of resources and expertise throughout the hospital, including:
- diverse populations of well-characterized patients with brain disorders
- clinical genetics and genomics expertise
- MRI and radiology expertise
- clinical bioinformatics
- tissue banks
- animal models
- stem cell platforms
- cognitive neuroscience laboratories
- deep knowledge of rare diseases, both clinical and scientific
- top clinical and basic scientists
Together, the services described below provide infrastructure for basic scientists and clinicians to collaborate in bringing discoveries from bench to bedside. The RSZ TNC’s overall goal is to create the infrastructure for a discovery pipeline from the identification of therapeutic targets and development of potential therapeutic agents to patient selection, clinical trial design and execution for Phase I and Phase II clinical trials. For any questions or to request access to RSZ TNC services, please contact us at TNC@childrens.harvard.edu.
Mustafa Sahin, MD, PhD, Director
Elizabeth Buttermore, PhD, Associate Director
Lee Barrett, PhD, Assistant Director, Assay Development and Screening Facility
Cidi Chen, PhD, Assistant Director, CRISPR (Services coming in 2022)
Nina Makhortova, MD, PhD, Assistant Director, Phenotyping Services
Dosh Whye, MS, Assistant Director, Differentiation Services
The Human Neuron Core at Boston Children’s Hospital offers a new paradigm for disease modeling and preclinical drug screening informed by broad expertise at Harvard in neuroscience, neurology and stem cell biology. Generous funding from the Massachusetts Life Sciences Center has enabled us to significantly expand our equipment and services and open them to the broader research community. The Core offers transformative stem cell technology for both modeling of specific diseases and screening of test compounds in human neurons derived from induced pluripotent stem cells (iPSCs).
- The Human Neuron Differentiation Service provides well-characterized human neurons to academic investigators and industry collaborators to support translational research programs. Cell types available include human neurons derived from induced pluripotent stem cell (iPSC) lines, including excitatory cortical neurons, GABAergic neurons, spinal motor neurons, and sensory neurons.
- The Human Neuron Phenotyping Service can compare key cellular characteristics across patient-derived and control-derived neurons. Phenotyping services include quantification of high content measures of neuronal morphology, neuronal excitability using multiple electrode array recordings and targeted RNA sequencing profiles (AmpliSeq) of neuronal transcriptomes. Equipment is also available for core users to run experiments independently.
- The expanded Assay Development Screening Facility provides multiple live-cell screening platforms that can assess image- and activity-based measures of live neurons hourly, in a medium/high-throughput capacity. Key equipment available for hourly use includes the Hamamatsu Functional Drug Screening System and the Molecular Devices IXM-C, a high content screening platform with live cell imaging and support from a range of robotics and liquid handlers to operationalize drug screening efforts.
- The Repository Core for Neurological Disorders is a Boston Children’s Hospital database and biological specimen bank that pairs biological samples with phenotypic data for translational research and clinical trials. To better understand causes and create new therapies for neurological disorders, it is often necessary for researchers to investigate various patients with the same or similar conditions. Therefore, such studies can benefit immensely from access to a database of high-quality clinical data paired with DNA and protein samples from affected individuals. This database and bio-specimen bank can save both time and resources that would be required to collect these data independently. As a result, all data, DNA and other bio-samples will be stored indefinitely and will potentially be used by multiple investigators for future studies of the causes and/or treatment of neurological disorders. The Core is anticipated to lead to new and enhanced collaborations among users, including collaborations between those who submit and those who access the data, between those who analyze the data with different primary goals, and between those using this and other Cores.
The core aims to become a leader in the acquisition and analysis of high-quality human neurophysiological data, specializing in the acquisition of EEG from infants, children and individuals with neurodevelopmental disorders. The Core occupies a purpose-built space at 2 Brookline Place outfitted with a high-density electrophysiology system that provides integration with stimulus presentation (for event related potentials) and eye tracking. The Core offers experimental design/grant consultation, acquisition of EEG from infants, children and adults and data analysis.
- Neurophysiology Experimental Design/Consultation
- Neurophysiology Study Start Up (coding paradigms, optimizing equipment)
- High-density EEG Acquisition (MagStim EGI Geodesic High Density EEG System)
- Equipment Use (EGI EEG System, Physio16 Physiological Measurement Hardware, Presentation Software, EyeLink Eye Tracker, Emblettea MPR PSG System-XD)
- EEG Data Analysis
In parallel, through a collaboration with the IDDRC Animal Behavioral and Physiology core, the Unit has the capability of recording long-term, wireless video-EEG from 20 mice simultaneously for the assessment of genetic or pharmacological manipulations on neural activity. To parallel the clinical methodologies, rodent EEG can be combined with stimulus presentation and TMS experimental designs. The Unit also provides consultation regarding trial design, rationale for a neurophysiology measure relevant to target disorder or developmental process, assessment of data-acquisition needs including contextual review of the literature and current competitive efforts elsewhere, identification of research collaborators, and recommended software or platform for processing.
Clinical Research Operations
Stephanie Jo Brewster, MS, CGC, Director
Clinical Research and Regulatory Affairs Service
This service facilitates the mission of the RSZ TNC, providing the necessary regulatory guidance and training for the successful implementation of new and ongoing clinical studies. Additionally, the team members serve as leadership for the Neuroscience Clinical Research Cluster and the Clinical Translational Core of the Intellectual and Developmental Disabilities Research Center (IDDRC) for Boston Children’s Hospital. The service is led by experts in protocol development and launching of new studies. Staff are available to guide RSZ TNC affiliated researchers in designing clinical research projects and the preparation of Institutional Review Board (IRB) and FDA submissions. Additionally, staff assist researchers with recruitment plans, study monitoring and audit preparation. Through monthly program managers’ meetings, this service regularly evaluates best practices in the conduct of clinical research. Staff members also facilitate access to other RSZ TNC resources including the Human Neurobehavioral Core Service and Biorepository, as well as additional research resources at Boston Children’s.
- regulatory guidance around federal, state and institutional policies including Good Clinical Practice
- consultation regarding protocol and consent form development
- facilitation of Institutional Review Board (IRB) and FDA submissions
- implementation of new studies
- project management
- development of training materials and workshops for study personnel
- facilitation of patient recruitment
Human Neurobehavioral Core Service
The goal of the Human Neurobehavioral Core Service (HNBCS) is to improve and expand access to behavioral assessment resources for translational neuroscience research at Boston Children’s Hospital. HNBCS represents a collaboration between the Laboratories of Cognitive Neuroscience and Neurodevelopmental Disorders Phenotyping Program in the Division of Developmental Medicine and the Clinical Behavioral Science Core in the Department of Psychiatry. The core is led by experts in the standardized administration of numerous testing measures and offers a comprehensive array of assessments for individuals from birth through adulthood. These measures include cognitive, behavioral, neuropsychiatric, social, adaptive, language, motor and academic functioning, among others. HNBCS has certified administrators and trainers in the Autism Diagnostic Observation Scale – Second Edition (ADOS-2) and Autism Diagnostic Interview – Revised (ADI-R) as well as a number of other assessments requiring extensive training. HNBCS operates a rigorous training and fidelity program for staff which includes reliability procedures, behavioral management techniques and extensive education on diverse patient populations.
- staff with expertise in the development, administration and analysis of neurobehavioral assessments for a wide variety of studies including clinical trials, natural history projects, phenotypic characterization, outcome studies and behavioral therapeutic interventions
- consultation on all aspects of study design including research protocol and study aims development; choosing which assessment measures will best capture characteristics desired for analysis; and developing relevant budgets
- expertise in which tests provide the best translation from animal to human studies
- training of study teams on select neurobehavioral measures
- identification of specialized laboratories at Boston Children’s providing novel tests
Research Participant Registry (RPR)
The RPR is a recruitment registry of >30,000 individuals (children and adults) with typical and atypical development who are interested in research participation. The Registry serves as a vital recruitment resource for investigators enrolling individuals of all ages with neurodevelopmental challenges as well as those who are typically developing.
Translational Genomic Medicine Unit
Maya Chopra, MD, FRACP, Director
The Translational Genomic Medicine (TGM) Unit offers genomic / clinical genetics expertise for clinical and translational research projects focused on rare monogenic neurodevelopmental disorders within Boston Children’s Hospital as well as across other institutions. Current projects include the CTSA-IDDRC National Brain Gene Registry for which the TGM Director serves as the Genomic Medicine Lead. The TGM Unit has experience in building multi-disciplinary clinics and establishing international partners for rare genetic disease research, as demonstrated by the establishment of the Kleefstra syndrome (KS) Research and Clinical Program and KS International Consortium. This Unit closely interacts with other TNC services including the Human Neuron Core for the evaluation of suitability of rare disease patient-derived samples for developing cell lines, in terms of determining whether variants sufficiently represent the target population being studied. In partnership with BCH investigators, expertise in rare disease sequencing projects, including exome pipeline analysis, precision phenotyping, variant analysis / interpretation and clinical referral pathways for actionable results is also offered.
- Consultation for establishment of multi-disciplinary rare disease / convergent pathway clinics
- Clinical genetic expertise for incoming proposals for preclinical research, natural history studies and gene based clinical trials for rare monogenic NDD
- Clinical practice improvement consultation, particularly for development of framework for genetic evaluation of NDD populations
- Identifying and establishing local and international partnerships and collaborations for rare NDD genetic disease research
- Partnering in sequencing projects focussed on rare NDD cohorts
- Training and mentorship particularly the intersection of variant interpretation, and clinical genetics evaluation. Trainees / mentees would also have the opportunity to participate in an internationally recognized Gene Curation program, with Dr. Chopra serving as Chair of the new Brain Gene Registry ID/Autism Gene Curation Expert Panel