Ralph Weissleder
The development of novel high resolution molecular imaging systems, tools for early disease detection, new and more advanced nanomaterials for imaging, and modeling methods for systems analysis. Increasingly, his work has been focused on reconciling the gap that exists between traditional cell biology and human biology. His work on imaging, nanomaterials and miniaturized chips has already led to a number of advanced clinical trials. When these techniques become routinely available, they are anticipated to have a major impact on clinical practice. Dr. Weissleder is currently the principal investigator of several National Institute of Health (NIH) grants and consortia.
Projects
My goal for the next 5 years is to explore, develop and apply fundamentally new approaches to cancer biology. It is my aim to 1) to develop novel, first-in-class imaging probes for key targets and pathways in cancer cells (“imaging major hubs and pathways”); 2) to use these probes to study clinically relevant tumor biology in vivo such as cellular heterogeneity of cancer and host cells (“imaging at single cell resolution”); and 3) to provide insight into therapeutic response and resistance at the cellular level (“single cell pharmacodynamics”). Some specific research projects include:
Bioorthogonal small molecule in vivo imaging agents
By harnessing a recently developed bioorthogonal in vivo detection (BIND) chemistry, which involves the highly specific and fast reaction between strained trans-cyclooctene and tetrazine derivatized imaging reporters, we are developing cell permeable small molecule affinity ligand-based probes that are capable of targeting key “hubs” in cancer cells. Current efforts focus on imaging PARP1, PLK1, HDAC, BCL-2, CTSE among others. These targets were selected based either on their unique importance to cancer proliferation or on their use as a measurement of therapeutic efficacy. In aim 1, we will develop and test a library of compounds for imaging at the microscopic level. For aim 2, we will focus on the protein-wide identification and validation of binding partners of lead compounds, for which we will use BIND-enriched stable isotope labeling with amino acids in cell culture (SILAC) to perform cell-based and in vivo proteomics. These experiments are critical since a comprehensive understanding of the interacting proteins and their associated protein complexes is important for the development of imaging agents and the interpretation of imaging studies. Finally, in aim 3 we will explore the translational potential of hits using the imaging probes determined from above. These will be investigated under combination therapy in genetically engineered mouse models. We expect that the BIND technology platform will have considerable translational potential for the imaging of a wide variety of intracellular cancer targets.
Nanoscale real-time sensing using µNMR-chip technology
There is a need for better detection platforms for specific mammalian cells, bacteria and viruses implicated in human disease. Traditional tools such as culture and biochemical analysis are often slow, rely on fixed (i.e. dead) tissue and require skilled personnel or specialized facilities. Recently, several rapid testing platforms have been developed that have the potential to provide rapid diagnosis in any clinical setting, but they are either insufficiently sensitive or require extensive sample preparation. Recent advances in nanotechnology and microfluidics now make this possible. We have developed a miniaturized nuclear magnetic resonance system (µNMR) that is simple and sensitive enough to be used in a clinical point-of-care device, and is well suited to profiling very low numbers of live mammalian cells or pathogens in complex clinical material. Several clinical trials are ongoing including : 1) detection of TB in sputum samples in Africa; 2) detection of circulating cancer cells in peripheral blood; 3) exosome profiling in glioma patients undergoing treatment; 4) profiling of freshly harvested human cancer cells to measure treatment response to novel drugs.
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About Dr. Weissleder: He is a Professor at Harvard Medical School, Director of the Center for Systems Biology at Massachusetts General Hospital (MGH), and Attending Clinician (Interventional Radiology) at MGH. Dr. Weissleder is also a member of the Dana Farber Harvard Cancer Center, an Associate Member of the Broad Institute (Chemical Biology Program) and a member of the Harvard Stem Cell Institute (HSCI) leading its Imaging Program. Dr. Weissleder is a graduate of the University of Heidelberg, obtained his residency training at MGH and has been on staff at HMS since 1991. He has published over 600 publications in peer reviewed journals and has authored several textbooks. His work has been honored with numerous awards including the J. Taylor International Prize in Medicine, the Millenium Pharmaceuticals Innovator Award, the AUR Memorial Award, the ARRS President's Award, The Society for Molecular Imaging Lifetime Achievement Award, the Academy of Molecular Imaging 2006 Distinguished Basic Scientist Award among others. In 2009 he was elected member of the US National Academies Institute of Medicine.