A New Approach to Genome-Scale Modeling of Intracellular Signaling: Neural Networks Constrained by Prior Knowledge Interactomes
ABSTRACT: Mammalian cells adapt their phenotypic state in response to ligand stimuli binding cell surface receptors, inducing modulation of a complex network of intracellular molecular interactions that govern cell regulatory and functional processes. Computational modeling of the information flow through this network could help predict cell behaviors in health and disease. However, obtaining sufficient experimental data to construct reliable models comprising adequate parameterization continues to be a severe problem. To address this challenge, we have recently developed a new approach: integrating a neural network machine learning framework constrained by prior knowledge of the intracellular protein-protein interactome. This approach can generate an operational model based on ligand inputs and corresponding transcriptional profile outputs. We demonstrate utility in immune cell signaling applications, including macrophages and CAR T-cells, and describe potential wider use such as for tumor cells.
Biography (from the National Academy of Engineering)
Douglas A. Lauffenburger is the Ford Professor of Bioengineering in the Departments of Biological Engineering, Chemical Engineering, and Biology at MIT. He was the founding head of the Department of Biological Engineering and served in that capacity from 1998 until 2019. He also holds affiliations with the Center for Biomedical Engineering, Center for Gynepathology Research, and Koch Institute for Integrative Cancer Research at MIT, as well as the Ragon Institute of MGH, MIT, and Harvard. Before joining MIT in 1995, he was a member of the faculty at the University of Pennsylvania (1979–90) and University of Illinois at Urbana-Champaign (1991–94).
A central focus of the Lauffenburger research program is systems biology approaches to cell-cell communication and cell signaling important in pathophysiology, with emphasis on translational application to therapeutics discovery and development in cancer, pathogen infection, and inflammatory disease.
Dr. Lauffenburger coauthored the monograph Receptors: Models for Binding, Trafficking, and Signaling (Oxford Press, 1993) and coedited the book Systems Biomedicine: Concepts and Perspectives (Elsevier Press, 2010). More than 130 doctoral students and postdoctoral associates have undertaken research education under his supervision.
He has served as president of the Biomedical Engineering Society, chair of the College of Fellows of American Institute for Medical and Biological Engineering, a member of the advisory council for the National Institute of General Medical Sciences, and a coauthor of the 2009 National Research Council report A New Biology for the 21st Century. He has also been a scientific advisor to numerous biotech/pharma companies and biomedical science foundations.
Along with many honors and awards from professional societies, Professor Lauffenburger is a member of the NAE and American Academy of Arts & Sciences, and a fellow of the American Association for Advancement of Science and the American Scientific Affiliation.
Professor Lauffenburger’s BS and PhD degrees are in chemical engineering, from the University of Illinois (1975) and the University of Minnesota (1979) respectively.