In September of 2018, the PCMI initiative received its first major funding award, a Collaborative U01 award as part of the Convergent Neurosciences Consortium at the National Institute of Mental Health (NIMH) at National Institutes of Health (NIH). The aim of the grant is to identify the functional pathways and molecular networks that autism spectrum disorder (ASD) genes participate in and relate them to higher order phenotypes, all the way to models of the human brain.
This grant is a multi-PI initiative headed up by Nevan Krogan, Jeremy Willsey and Martin Kampmann at UCSF, along with Trey Ideker of UCSD. This dynamic team brings together a range of expertise and experience that is helping break down silos and bring about breakthroughs in autism research.
U01 Autism Grant Leadership:
Dr. Nevan Krogan (Co-PI) is a Professor of Cellular and Molecular Pharmacology at UCSF as well as a Senior Investigator at the J. David Gladstone Institutes. He is also the Director of the Quantitative Biosciences Institute (QBI), an institute at UCSF dedicated to quantitative biology, as well as the Director of the Thermo Fisher Scientific Proteomics Facility for Disease Target Discovery, founded in 2015 by Thermo Fisher, UCSF and the Gladstone Institutes. Finally, he is Director of the NIHfunded P50 HARC (HIV Accessory and Regulatory Complexes). During his PhD studies at the University of Toronto under Jack Greenblatt, Krogan developed and used several systems approaches and integrated the resulting data to study many pathways in budding yeast. During his time as an independent Sandler Fellow at UCSF and then as a faculty member starting in 2007, he has since extended these approaches to different disease states in humans, including viral pathogenesis and cancer. He has identified important relationships between physical and genetic interaction data and is now using system biology to bridge clinical and mechanistic studies. He is a Searle Scholar and Keck Young Investigator and was recently named to the “40 Under 40” list by Cell. He serves on the editorial boards of several journals, including Molecular Systems Biology and Cell Systems and is routinely an organizer of international conferences including meetings at EMBL, in Asia and in the US. Dr. Krogan cofounded the PCMI (pcmi.ucsf.edu), as well as the CCMI (ccmi.org) and the HPMI (hpmi.ucsf.edu).
Jeremy Willsey (Co-PI) is an Assistant Professor in the Institute for Neurodegenerative Diseases (IND) and the Department of Psychiatry at UCSF. He has over 10 years’ experience in genetics and bioinformatics, including expertise in systems biological analysis of large datasets and in the analysis of highthroughput genetic data, especially for the detection of rare and de novo mutations. His research focuses on identifying and leveraging these mutations for locus and gene discovery in autism spectrum disorder (ASD), Tourette disorder (TD), and other neuropsychiatric disorders, and then applying systems biological approaches that integrate multidimensional datasets in order to understand the biological relevance of discovered loci or to improve our ability to detect additional risk genes. He has contributed to the discovery of over 65 ASDassociated genes and has recently led a whole exome sequencing analysis in TD that implicated, for the first time, de novo sequence variants in TD risk. This work also led to the identification of the first four TD risk genes identified by large-scale whole exome sequencing while working in Matthew State’s lab, he also led an effort to understand spatiotemporal convergence in ASD, which led to the pinpointing of deep layer glutamatergic neurons in the developing midfetal prefrontal cortex as a critical nexus of risk. His lab continues to develop and refine methods for identifying spatial-, temporal-, and cell-level convergence in ASD and other neurodevelopmental disorders, with the hope that this will inform our understanding of pathology, and eventually, treatment of these conditions. Jeremy cofounded the Psychiatric Cell Mapping Initiative (PCMI) along with Drs. Krogan and State, is on the executive committee of the Tourette International Collaborative Genetics Study (TIC Genetics; ticgenetics.org), and is a member of several large consortia including, PsychENCODE and the Whole Genome Sequencing in Psychiatric Disorders consortium.
Trey Ideker (Co-PI) is Professor of Genetics in the Department of Medicine at UCSD, as well as an Affiliate Professor of Bioengineering and Computer Science. He is Director of the National Resource for Network Biology (an NIHfunded P41), CoDirector of the San Diego Center for Systems Biology (an NIHfunded P50), CoLeader of the Cancer Genomes and Networks program at the UCSD Moores Cancer Center and a former Division Chief of Genetics in the Department of Medicine at UCSD. His career has spanned pioneering work in systems biology and a track record in innovative and widelyused bioinformatic tools. His research is led by the vision that with the right data and analysis, it will be possible to automatically assemble maps of whole biological systems just as we now assemble maps of genomes. Ideker received BS and MS degrees in Computer Science from MIT and a PhD at the University of Washington with Drs. Leroy Hood and Richard Karp. During this graduate work, Ideker built models of gene networks that laid the foundation for many future studies in systems biology. Later, using his Cytoscape platform he demonstrated that such networks could be aligned, like sequences, to reveal conserved and divergent functions, and that the best disease biomarkers are typically not single proteins but protein networks. Ideker was named a Top Ten Innovator of 2006 by Technology Review and received the Overton Prize in 2009, one of the highest awards in computational biology. He is on the editorial boards of Cell, Cell Reports, Molecular Systems Biology and PLOS Computational Biology.
Martin Kampmann (Co-PI) is an Assistant Professor in the Institute for Neurodegenerative Diseases (IND) and the Department of Biochemistry and Biophysics at UCSF. He was also named an Allen Distinguished Investigator by the Paul G. Allen Family Foundation in 2015, and a Chan Zuckerberg Biohub Investigator in 2017. Most recently, Dr. Kampann received the Ben Barres Early Career Acelerator Award from the Chan Zuckerberg Initiative. Dr. Kampmann has codeveloped CRISPRi/a based genetic screening technologies and pioneered genetic interaction mapping in mammalian cells based on pooled genetic screens. In his independent research group, he has implemented these functional genomics approaches in human iPSCderived neurons. Dr. Kampmann is also a member of the Tau Consortium, a large international and multidisciplinary consortium of scientists and clinicians investigating tau-related disorders, and funded by the Rainwater Foundation. Dr. Kampmann also directs the CRISPRi/a core of the NINDS-funded U54 Center Without Walls for Tau Biology, in which he applies CRISPRi/a screening technology in iPSC-derived neurons in the context of neurodegeneration.
Other team members include:
Dr. David Agard (Co-I) is a leader in the field of electron microscopy. His pioneering work with collaborators at UCSF has led to a “resolution revolution” in the field, achieving cryo-EM structures at atomic resolution. His work focuses on the development of innovative electron cryomicroscopy methodologies, tools and software and applying them to critical biomedical problems.
Jennifer Doudna (Co-I) is the Founder of the Innovative Genomics Institute (IGI) at Berkeley and UCSF. Her discovery of CRISPR biology as a simple, effective genetic engineering tool is the biggest genetic science breakthrough of the past two decades. This work has led to the publication of more than 1,500 research articles from laboratories around the world, several biotechnology companies and numerous international awards and recognition.
Dr. Steven Finkbeiner (Co-I) invented robotic microscopy, a powerful and fully automated platform for performing longitudinal single cell analysis and generating deep phenotypes from human neurons, organoids and simple organisms. Using an array of over 270 biosensors known as the physical exam of the cell, combined with robotic microscopy, deep learning, and convolutional neural networks, his group can quantify phenotypes that are difficult or impossible for humans to see.
Dr. Ruth Huettenhain (Co-I) is a young investigator in quantitative mass spectrometry and systems biology who has developed and applied innovative targeted proteomic technologies including novel proximity-based biotinylation approaches that are game-changing. Dr. Huettenhain has taken a leadership role in communicating and disseminating knowledge about these new techniques and has organized and participated in several symposia on mass spectrometry.
Dr. Michael Keiser (Co-I) combines machine learning and chemical biology methods to investigate how small molecules perturb entire protein networks to achieve their therapeutic effects. His laboratory develops new approaches to address core challenges in systems pharmacology, such as the elucidation of multi-target small-molecule mechanisms, integration of genomic and phenotypic data, and the delineation of pharmacological circuits.
Dr. Tomasz Nowakowski (Co-I) studies cellular diversity in the brain by applying innovative strategies for massively parallel profiling in primary human cortical cells using droplet-based technologies, cellular barcoding, viral vector-mediated gene delivery in primary cells and time-lapse microscopy.
Dr. Brian Shoichet (Co-I) is a computational chemist who has pioneered new methods to discover small molecules that can illuminate biology and contribute to therapeutic discovery. His group uses molecular docking and computational approaches to discover new ligands for known protein structures or new targets for known drugs and reagents.
Dr. Matthew State (Co-I) is the Chair of Psychiatry at UCSF and studies pediatric neuropsychiatric and neurodevelopmental syndromes, with a particular focus on the contribution of rare variation to autism spectrum disorders (ASD) and Tourette disorder. His group pioneered the use of these variants for systematic, reliable gene discovery, resulting in the association of more than 65 genes with ASD and the first high confidence gene in Tourette disorder.
Dr. Mark von Zastrow (Co-I) studies mechanisms involved in targeting and trafficking of neural signaling receptors, with a major focus on G-protein coupled receptors (GPCRs). His work focuses on analysis primarily at the cellular level and seeks precise mechanistic elucidation through a combination of biochemical, molecular biological, proteomic, light and electron imaging methods.
Dr. Helen Willsey (Co-I) is an award-winning young investigator who has been instrumental in establishing key technologies for studying neurodevelopment in Xenopus tropicalis at UCSF. By establishing a colony and pipeline for performing and analyzing results of CRISPR/Cas9 genome editing in Xenopus tropicalis embryos, her work enables understanding of gene function during neurodevelopment.
