Exploring Genomic Basis for Neurologic and Cardiovascular Disease using Reprogramming and Pluripotent Stem Cells
Home Is Where the Pipette Is
BALDWIN LAB AT A GLANCE
Our lab was the first to show that a full mouse could be successfully cloned from induced pluripotent stem cells (iPSCs). Ever since, we've leveraged the potential of reprogramming to explore questions of basic biology and translational medicine. From neuronal diversity to cardiovascular disease, from autism to the mutational spectra of aging, our lab tackles a wide variety of projects through the biologic alchemy of molecular reprogramming.
USING IPSCS TO MODEL CARDIOVASCULAR AND NEUROLOGIC DISEASE
Induced pluripotent stem cells capture the genome of the somatic cells of an individual and may be used to produce diverse cell types to explore the impact of human genetic diversity on a wide variety of diseases. We have been generating iPSCs from a cohort of patients called the "Wellderly" in collaboration with the lab of Eric Topol. We are investigating the impact of long life and healthy aging on the somatic genomes of these individuals
In a second project recently published in Cell, we have been employing genome editing to address the role of a risk locus for coronary artery disease. These lines and our experience with genome editing open the door to better modeling for other later onset diseases of interest such as Alzheimer's and Parkinson's disease.
UNDERSTANDING NEURAL DIVERSITY: A PERIODIC TABLE OF THE BRAIN
Our lab is interested in understanding how epigenetic changes result in a defined yet limited number of distinct neuronal cell states. One approach we use is direct conversion of fibroblasts to functional neurons in combination with gene expression analyses of defined neuronal subtypes.
In a recent Nature paper we showed that various combinations of transcription factors could yield reproducible, distinct populations of neurons. Our current efforts dramatically expand the scope of this study with the aim of generating a comprehensive understanding of how to derive all of the brain's neuronal subpopulations through reprogramming. Harnessing the versatility of induced neurons will allow us to further explore cellular identity, relevant human behavior, drug discovery and disease.
UTILIZING MOUSE/RAT CHIMERAS TO BETTER UNDERSTAND NEURAL CIRCUITRY
How are distinct populations of neurons integrated into the broader neural circuitry? Understanding this fundamental biology will be pivotal to unraveling the mysteries of cognition. One way to address this topic is to generate interspecies chimeras and observe how the neuronal population from one species interacts with the neural architecture of the host. To that end we have derived a cohort of rat/mouse chimeras and examined how rat olfactory neurons contribute to the mouse olfaction.
ASSESSING THE GENOME OF THE AGING BRAIN
Neurons exhibit unusual cellular diversity, are largely born early in development and persist without cell division for he lifetime of an organism. Yet, due to their post-mitotic status, little is known about their genomes owing to the myriad challenges of single cell sequencing. Genetic variability between individual neurons, and the fact that the genome changes throughout aging, is increasingly recognized as a contributor to neurodevelopmental disorders and potentially to neurodegeneration. Studies in our lab have demonstrated that the genome of a post-mitotic neuron can re-enter the cell cycle and be reprogrammed to a state of totipotency after nuclear transfer.
Utilizing somatic cell nuclear transfer (SCNT) and next-generation sequencing technology enables us to examine the mutational landscape and genomic plasticity of neurons at a single cell level with high resolution.
Utilizing SCNT, we previously showed that mouse mitral and tufted neurons possess few structural variants and mobile element insertions, but have roughly 60-100 single nucleotide variants (SNVs). Current work is focused on extending this technique to include additional neuronal subtypes at different ages and disease states.