Chemical Biology Seminar: Professor Timothy Springer, Harvard University
About the Seminar
"Integrins and new tools for organoids"
Artificial substrates featuring the bacterial protein invasin or integrin-activating antibodies promote organoid formation. Cryo-EM structures of invasin-bound integrin α6β1 and α5β1 reveal invasin’s unique binding to both integrin β1 and α subunits, despite interacting with eight β1 integrins. Single molecule and bulk analyses show invasin binds to the bent-closed integrin state and shifts it to the extended-open state with ultra-high preference compared to native ligands. Similarly, open-stabilizing integrin antibodies in Matrigel enhance organoid formation. These findings unveil principles for designing novel agents to stimulate organoids and guide development of mixed-lineage organoids.
About the Speaker
Timothy A. Springer, Ph.D. is the Latham Family Professor in the Departments of Pediatrics and of Biological Chemistry and Molecular Pharmacology at HMS and at BCH is in the Program of Cellular and Molecular Medicine and Division of Hematology. Tim discovered and functionally characterized many of the adhesion receptors in the immune system with monoclonal antibodies. He was the first to demonstrate that lymphocytes, leukocytes and endothelium had adhesion molecules and went on to discover the three step paradigm for leukocyte diapedesis: rolling on selectins, activation by chemokines, and firm adhesion and transmigration across endothelium on integrin adhesion receptors. His work on integrins has advanced to characterizing their interactions and allosteric transitions by x-ray crystallography, electron microscopy, and single molecule fluorescence resonance energy transfer (FRET). He was elected to the National Academy of Sciences and his awards include the Crafoord prize, the Stratton Medal from American Society of Hematology, the Canada Gairdner International Award, the Lasker Basic Medical Research Award, and the Robert Koch Award. He has been a founder and/or investor in LeukoSite, Moderna Therapeutic, Editas Medicine, Scholar Rock, Morphic Therapeutic, Tectonic Therapeutic, and Seismic Therapeutic. His research and company formation has led to six FDA-approved drugs, including antibodies for treating cancer and immune diseases. Philanthropically, he founded the Institute for Protein Innovation, a non-profit advancing synthetic antibody discovery for biomedical research and protein science. He has endowed Professorships and Chairs at Harvard Medical School, UC Berkeley, and Boston Children’s Hospital, and has served on the Boston Children’s Hospital Board of Trust.