The long-term goals of the work I will discuss are three-fold– in development, disease, and regeneration: 1) to elucidate central molecular mechanisms controlling development and diversity of cerebral cortex function-specific circuitry, thus organization and evolution (to some extent) of the cerebral cortex; 2) to identify causes/mechanisms of developmental dysgenesis and selective neuron subtype vulnerability in many neurodegenerative disorders; and 3) to elucidate and potentially overcome blocks to CNS regeneration. The specificity, modification, and function of such circuitry underlies how the brain-nervous system senses, integrates, moves the body, thinks, functions with precision, malfunctions with specificity in disease, degenerates with circuit specificity, might be regenerated, and/or might be modeled in culture, but has been previously inaccessible in multiple core aspects. What actually implements and maintains circuit specificity is a key, core issue from developmental specificity of circuits, to developmental abnormalities and disease, proper function (or dysfunction) and circuit type-specific molecular regulators and drugs, selective neuron type vulnerability of degeneration (e.g. in MND/ALS), regeneration (or typical lack thereof) in the CNS for spinal cord injury, and mechanistic and therapeutic modeling of disease using human induced pluripotent stem cell (hiPS)-derived neurons.
Growth cones (GCs) are the subcellular structures that “build” circuits with specificity and mature into synapses, where human genomic risk associations are showing up in neuropsychiatric diseases such as schizophrenia, autism, bipolar disorder, developmental intellectual disabilities, but we know little about the diversity and specialization of circuit-specific GCs or synapses. I will present a brief integration of recent work investigating subtype-, stage-/context-, and target-specific GCs and synapses in development, neuronal and circuit diversity, disease, regeneration, and newly enabled hiPS-based fused organoid “assembloids” to address these critical gaps in knowledge. I will dabble a bit in discussing evolution here and there. We have developed and integrate several new approaches (e.g. subtype- and stage-specific subcellular RNA, protein, translational regulation, “specialized” ribosome analysis of GCs / synapses directly from brains; mosaic genetic circuit analysis; hiPS “assembloids” with somewhat selective connectivity) to investigate basic “framing rules” of diverse function-enabling CNS circuitry, potentially explain selective vulnerability in developmental and degenerative nervous system diseases, and potentially enable CNS regeneration.
Jeffrey D. Macklis is the Max and Anne Wien Professor of Life Sciences, and Professor of Stem Cell and Regenerative Biology in the Department of Stem Cell and Regenerative Biology, and Center for Brain Science, Harvard University, and Professor of Neurology [Neuroscience] at Harvard Medical School (HMS). He was founding Program Head, Neuroscience, Harvard Stem Cell Institute. He is Director of Graduate Studies in the Department of Stem Cell and Regenerative Biology, and (co-)Director of the Developmental and Regenerative Biology Ph.D. Program at Harvard University. He is an M.I.T. affiliate faculty member in the Harvard-Massachusetts Institute of Technology (M.I.T.) Division of Health Sciences and Technology (HST) and M.D.-Ph.D. Program.
His lab is directed toward both: 1) understanding molecular controls and mechanisms over neuron sub-type specification, development, diversity, axon guidance-circuit formation, and degeneration in the cerebral cortex; and 2) applying developmental controls toward both brain and spinal cord regeneration and directed differentiation for in vitro therapeutic and mechanistic screening. The lab focuses on neocortical projection neuron development and sub-type specification; neuronal subcellular molecular machinery for subtype- and stage-specific circuit formation, maintenance, and function; neural progenitor / “stem cell” biology; induction of adult cortical neurogenesis; subtype-specific axonal growth cone biology; and directed neuronal subtype differentiation via molecular manipulation of neural progenitors and pluripotent cells (ES/iPS).
He attended M.I.T. as an undergraduate (S.B. Bioelectrical Engineering; S.B. Literature), Harvard Medical School (Harvard-M.I.T. HST Program), and graduate school at M.I.T. within HST, a student of Richard L. Sidman. He was a postdoctoral fellow in developmental neuroscience at HMS, where he also trained clinically in Internal Medicine at Brigham and Women’s Hospital (BWH) and Neurology in the Harvard Neurological Training Program (he is no longer clinically active).
He is the recipient of a number of awards and honors, including a Rita Allen Foundation Scholar Award, a Director’s Innovation Award from the NIH Director’s Office, the CNS Foundation Award, a Senator Jacob Javits (MERIT) Award in the Neurosciences from NINDS/NIH, the Cajal-Krieg Cortical Discoverer Prize, and a series of undergraduate and graduate teaching and research mentoring prizes over the past 25 years. He is an Allen Distinguished Investigator of the Paul G. Allen Frontiers Group, a Brain Research Foundation Fellow, and recipient of an NIH Pioneer Award from the Office of the NIH Director.