Our laboratory is broadly interested in the mechanisms underlying changes in the nervous system as a result of aging or disease, as well as the interactions between the nervous system and the rest of the body that mediate health versus disease. Studies involve a variety of in vivo, in vitro, and in silico approaches to generate insights into the complex molecular pathways underlying different disease states with a goal of identifying novel therapeutic avenues. Current efforts in the lab include studies of the aging brain, CNS disorders (including neuromuscular, neurodegenerative and psychiatric) and skeletal muscle disorders.
Lee Rubin, Ph.D.
- Professor of Stem Cell and Regenerative Biology
- Executive Committee Member and Program Leader
Harvard Stem Cell Institute
Lee Rubin investigates the key molecular mediators of different neurodegenerative diseases, with the ultimate goal of finding effective preclinical therapeutic candidates. His research group discovered that a circulating protein, GDF11, has the ability to reverse some of the changes in the CNS associated with aging. They are actively exploring the therapeutic implications of these observations.
The Rubin group takes advantage of their ability to produce large numbers of patient-derived induced pluripotent stem (iPS) cell lines and of effective means of deriving large numbers of differentiated neurons from them. They have set up an array of techniques that allow them to identify early cellular and physiological changes in neurons as they become diseased. For example, they have identified new targets for the treatment of the motor neuron disorders Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS). They are also studying Autism Spectrum Disorders, Parkinson’s disease and Alzheimer’s disease.
Dr. Rubin received his Ph.D. in Neuroscience from The Rockefeller University and completed postdoctoral fellowships in Pharmacology from Harvard Medical School and in Neurobiology from Stanford University School of Medicine. He has a broad experience in both academia and industry, particularly in the realms of cell-based assays and drug discovery. Prior to coming to Harvard, Rubin was Chief Scientific Officer of Curis, Inc., a Cambridge-based biotechnology company, where his group identified the first small molecule regulators of the hedgehog signaling pathway. One of their antagonists was developed by Genentech and is now (as Erivedge) approved as the first oral treatment for metastatic basal cell carcinoma.
Neuromuscular DisordersWe are developing novel models of neuromuscular disease using patient iPS-derived motor neurons (MNs), and performing high throughput screens to identify compounds that promote MN health and survival. The goal of these studies is to elucidate common molecular mechanisms underlying neuron degeneration and to identify compounds and cellular targets with therapeutic potential.
SchizophreniaTo start to unravel the connection between the complex genetics and the phenotypes observed in schizophrenia patients, we utilize human iPS cells and small molecule screening assays. We are currently exploring the complement component 4 (C4) gene, which is associated with a high risk of schizophrenia, in stem cell-derived astrocytes and neurons.
Parkinson’s DiseaseWe are using dopaminergic neurons derived from Parkinson’s disease (PD) patient iPS cells to model how the genetic differences between individuals confer risk for specific environmental exposures. We are our utilizing the laboratory’s screening expertise to examine dopaminergic neurons with the goal of uncovering new gene-environment interactions in PD.
Skeletal MuscleNeuromuscular disorders, such as Spinal Muscular Atrophy (SMA), often comprise a skeletal muscle defect in addition to the problems in the nervous system. SMA patients present with widespread muscle atrophy and weakness. Skeletal muscle tissue is known to regenerate rather well, a capability that is attributed to the activity of satellite cells, the resident skeletal muscle stem cell. We are carrying out studies to evaluate whether or not defects in satellite cells may contribute to neuromuscular diseases. Our research combines the use of SMA patient-derived iPSCs, genetic mouse models, and phenotypic drug screening methods.
Small Molecule Screening AssaysWe have established an extensive range of complex, image-based assays to probe the properties of stem cells and cells derived from them. We use automated, high-content screening imagers, associated robotic equipment, and selected small molecule libraries and combine this high throughput approach with detailed molecular studies to further our understanding of the mechanisms of disease and determine which compounds are most likely to be of therapeutic value.