Investigators & Fellows

2015 ADI Neuronal Maturation Cohort

The 2015 cohort of Allen Distinguished Investigators (ADI) awards are all in the field of neuronal maturation: a foundational field in neuroscience that seeks to improve how we cultivate and study mature human neurons in the laboratory. Advances in neuronal maturation are poised to dramatically impact how researchers study the healthy human brain, as well as enable breakthroughs in the treatments of diseases like autism, Alzheimer’s and Parkinson’s.

Allen Distinguished Investigators are passionate thought leaders, explorers, and innovators who seek world-changing breakthroughs. With grants between $1 million and $1.5 million each, the Foundation provides these scientists with enough funds to produce momentum in their respective fields.

Investigator: Daniel Geschwind and Steve Horvath, University of California, Los Angeles

Geswind
Daniel Geschwind Steve Horvath

Project title: Transcriptomic and Epigenetic Acceleration of Neuronal Maturation and Aging

Project description: One of the major obstacles to using human stem cells in the laboratory is that even the best protocols yield immature or inconsistent cells. Geschwind and Horvath are using mathematical predictions to identify factors that drive neuronal maturation in the human brain but that are absent in neurons grown from stem cells in cell culture. They will use these factors to create more stable cultures that are more similar to functioning neurons in the brain. They have also identified an aging clock based on genetic measurements from thousands of cells and tissues, and will use similar methods to mimic the effects of aging in the laboratory.

Investigator biographies:

Dr. Daniel Geschwind is the Gordon and Virginia MacDonald Distinguished Professor of neurology, psychiatry and human genetics at the UCLA School of Medicine. He is director of the Neurogenetics Program and the Center for Autism Research and Treatment (CART) and co-director of the Center for Neurobehavioral Genetics in the Semel Institute at UCLA. His laboratory aims to develop a mechanistic understanding of neuropsychiatric diseases both via human genetic studies and in vivo and in vitro model systems, such as neural progenitors. The lab’s approach relies heavily on computational and bioinformatic methods, including gene network analysis in addition to wet laboratory experimentation. He received the Derek Denny-Brown Neurological Scholar Award from the American Neurological Association in 2004, the Scientific Service Award from Autism Speaks in 2007, the Ruane Prize for Child and Adolescent Psychiatric Research from the Brain and Behavior foundation in 2012 and is an elected member of the Institute of Medicine of the National Academies.

Dr. Steve Horvath is a Professor in the Departments of Human Genetics and Biostatistics at the University of California, Los Angeles. His research lies at the intersection of computational biology, genetics, epidemiology, and systems biology. He works on all aspects of biomarker development with a particular focus on genomic biomarkers of aging. He recently published an article that describes a highly accurate biomarker of aging known as epigenetic clock. Salient features of the epigenetic clock include its high accuracy and its applicability to a broad spectrum of tissues and cell types. Dr. Horvath's most recent work demonstrates that the epigenetic clock captures aspects of biological age.

Award amount: $1,223,866

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Investigator: Feng Zhang, Massachusetts Institute of Technology

Feng Zhang
Feng Zhang

Project title: Genome-Scale Technologies for Reverse-Engineering Transcriptional Logics Underlying Cell Fate Specification

Project description: Understanding the biological mechanisms of neuronal differentiation and maturation is fundamental to rapidly replicating the diversity of cells in the human brain. Zhang’s project focuses on developing a highly scalable genomic engineering system that can reliably evaluate the genetic activity that leads to differentiated and matured cells, as well as produce differentiated and matured cells by modifying this genetic activity. He will apply the transcriptome analysis and powerful perturbation systems previously developed in his lab to study and later generate a number of human neuronal cell types relevant to neurological disorders.

Investigator biography: Feng Zhang is the Keck Career Development Professor of Biomedical Engineering at MIT, an Investigator of the McGovern Institute for Brain Research, a New York Stem Cell Foundation-Robertson Investigator, and a Core Member of the Broad Institute of MIT and Harvard. As a graduate student at Stanford University, Zhang worked with advisor Karl Deisseroth to invent a set of technologies for dissecting the functional organization of brain circuits. His lab works on developing and applying disruptive technologies including optogenetics and genome engineering (TALE and CRISPR) to understand nervous system function and disease. Zhang’s long-term goal is to develop novel therapeutic strategies for disease treatment. He obtained a bachelor’s degree from Harvard University and a PhD in chemistry and bioengineering from Stanford University. Before joining the MIT faculty he was a junior fellow of the Harvard University Society of Fellows. He is widely recognized for the development of molecular technologies including optogenetics and CRISPR-Cas9, including receiving the Waterman Award from the National Science Foundation, the Perl/UNC Prize in Neuroscience, and the Gabbay Award in Biotechnology.

Award amount: $1,001,726

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Investigator: Jeffrey Macklis, Harvard University
Jeffrey Macklis
Jeffrey Macklis

Project title: Cellular “Flight Data” Recorder, Checkpoint Timing, Hodaptics, and Growth Cone Independence

Project description: Macklis’ project has four proposed aims. The first is to develop a molecular-DNA "flight data recorder" inserted into individual cells, both to observe the rare cells that undergo remarkably appropriate partial maturation, and those that becomes stalled, confused, delayed, or immature. The second aim builds molecular timekeepers in order to better understand maturation time for individual cells. The third aim develops entirely novel synthetic biology technology to discover biological interactions during development that neurons may require to sequence through maturation “checkpoints.” The fourth aim develops first-in-field analysis of neuronal diversity and maturation at a deep level, in order to understand the basis of brain wiring and circuitry.

Investigator biography: Dr. Jeff Macklis is the Max and Anne Wien Professor of Life Sciences in the Department of Stem Cell and Regenerative Biology, and Center for Brain Science, Harvard University, and Professor of Neurology and of Neurosurgery at Harvard Medical School (HMS). His laboratory 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. Dr. Macklis 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, a Soderberg Prize Symposium Lectureship at the Swedish Society for Medicine, The CNS Foundation Award, numerous honorary and named institutional lectureships and visiting professorships (e.g. Leonardo da Vinci, Raine, Moon, Grass, Stellar, Sherman), several Hoopes Prizes for excellence in undergraduate research mentoring, and a Senator Jacob Javits Award in the Neurosciences and MERIT Award from the NINDS/NIH.

Award amount: $1,511,925

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Investigator: Erik Ullian and David Rowitch, University of California, San Francisco
 
Erik Ullian David Rowitch
Erik Ullian David Rowitch

Project title: Matching Regional Diversity with Function: Unique Astrocyte Signals Mature Regionally Matched Neurons

Project description: Astrocytes are the most abundant cell type in the human brain, providing signals that are essential for all aspects of neuronal function and survival. But just as no two neurons are the same, astrocytes are incredibly diverse and specialized. Different types of astrocytes can provide different kinds of support and signals to the neurons they surround. In this proposal, Ullian and Rowitch will test whether the signals from different types of human astrocytes are necessary for the proper maturation and function of human iPSC-derived neurons. Their previous work in mouse models indicates that generating astrocytes that are matched to their partner neurons will be essential to studying and understanding human neuronal function in both health and disease.

Investigator biographies:

The Ullian lab has experience using a variety of tools to ask what effect astrocytes have on neuronal function. As a postdoctoral fellow in Ben Barres’ laboratory at Stanford University Dr. Ullian studied the role of astrocyte signals that regulate the formation, function, and stability of neuronal synapses. This work led the fundamental principal that astrocyte play important roles in synapse formation and function and further led to the identification of the first astrocyte secreted molecule that impacts synapse number. More recently, as PI on several NIH and private foundation sponsored research grants Dr. Ullian has continued to investigate mechanisms regulate synapse number and neuronal function, establishing techniques for the labeling of subsets of cells for in vivo and in vitro analysis. His lab has published electrophysiological and anatomical studies of neurons from many brain regions adapting physiology to study important questions about astrocyte or neuronal function. Additionally, he has utilized iPSCs to derive human neurons and astrocytes to study the functional consequences of human astrocyte signals on neuronal and circuit maturation and function. These combined studies have led to the Allen Family Foundation proposal to investigate human astrocyte heterogeneity as a key signal for the functional maturation of regionally matched human neurons.

Dr. Rowitch is Professor of Pediatrics and Neurosurgery and Chief of Neonatology at the University of California, San Francisco. His research focuses on overlapping mechanisms of glial development and human neurological disorders and brain cancer. Previously, Dr. Rowitch was a faculty member and investigator at Harvard Medical School and Dana-Farber Cancer Institute in Boston. Dr. has recently been given the title of Vice-chair in Pediatrics for Laboratory Research at UCSF.

Award amount: $1,015,803

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Investigator: William Lowry and Kathrin Plath, University of California, Los Angeles
 
William Lowry Kathrin Plath
William Lowry Kathrin Plath

Project title: Identifying and Inducing Hallmarks of Maturity in Human Neurons

Project description: Another obstacle to creating useful pluripotent stem cells is purity, since it is nearly impossible to create pure populations of particular subtypes of neurons or glia, and those that are generated are more similar to those found during early fetal development as opposed to the cells that are needed clinically. Lowry and Plath have devised a model system to isolate and identify very specific types of neurons, which they can use to create neurons that are more like those found in the adult nervous system. These particular types of neurons are thought to be dysfunctional in various disorders including autism, Alzheimer’s and schizophrenia, so increased knowledge of these specific neurons could dramatically facilitate the study and eventual treatment of these devastating disorders.

Investigator biographies:

Dr. Lowry is an Associate Professor in the Department of Molecular Cell and Developmental Biology at the University of California-Los Angeles. His research focus is in modeling development and disease. A primary focus interest of this work is to understand the diversity and maturation process of human interneurons made in vitro.

Dr. Kathrin Plath is a Professor in the Department of Biological Chemistry at the University of California Los Angeles. Her research is directed at understanding the fundamental mechanisms that determine gene expression changes during cell fate transitions with a particular focus on enhancer utilization and the role of long-noncoding RNAs. A main interest of this work is to use enhancer signatures to define the diversity and maturation of specific classes of neurons. Dr. Plath also serves on the Board of Directors of the International Society for Stem Cell Research.

Award amount: $1,324,000

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Investigator: Thomas Reh, Rachel Wong and Fred Rieke, University of Washington
 
Thomas Reh Rachel Wong Fred Rieke
Thomas Reh Rachel Wong Fred Rieke

Project title: Using miRNAs to Accelerate in vitro Circuit Maturation in 3D Neural Structures from ESCs

Project description: This project will address two major roadblocks in neuronal maturation—diversity of cells in the brain and the developmental “clock”—in the context of the retina. The retina is ideal for these studies because it is a self-contained part of the nervous system with known cell types and stereotypic connections that have well-defined functions. The project will determine how closely the neural circuitry in a stem cell-derived retina resembles its normal in vivo counterpart, and will also investigate whether small RNAs, called microRNAs, control the developmental clock of maturation in the retina. Understanding the function of microRNAs in the retina, which appear to control the clock of maturation throughout our lives, will lead to better models of neurological diseases of aging and provide a basis for building a functional nervous system in the laboratory.

Investigator biographies:

Dr. Thomas Reh is a Professor in the Department of Biological Structure at the University of Washington. His research is in neural development and regeneration. A primary focus of this work is to understand the mechanisms that control developmental time during mouse and human neurogenesis and use these findings to stimulate repair processes. Previously, Dr. Reh was a AHFMR Scholar and an Alfred P. Sloan Foundation Fellow, and more recently has been awarded the Board of Director's Award from the Foundation Fighting Blindness.

Dr. Rachel Wong is a Professor in the Department of Biological Structure at the University of Washington. Her research is focused on elucidating the cellular mechanisms that underlie the proper development, maintenance and regeneration of circuits in the vertebrate retina. A primary interest of this work is to understand the mechanisms that control neuronal maturation in vivo and in vitro, and apply this knowledge to circuit repair. Previously, Dr. Wong was a C.J. Martin and R.D. Wright Fellow (Australia), an Alfred P. Sloan and a Esther A. and Joseph Klingenstein Fellow.

Dr. Fred Rieke is a Professor in the Department of Physiology and Biophysics at the University of Washington and an Investigator of the Howard Hughes Medical Institute. His research focuses on neural computation - particularly how neural circuits support the impressive sensitivity of our sensory systems. His lab focuses on both normal and aberrant signaling in the retina.

Award amount: $1,311,766