HSCI Alumni: Ralph Weissleder, MD, PhD
Harvard Medical School
We study human biology. Specifically, our current research is focused on the imaging and quantitative measurement of cancer biology and its treatment in vivo. My laboratory employs a variety of techniques including whole body and intravital microscopic imaging, novel chemical approaches for perturbing systems, and innovative sensing strategies including nanotechnology approaches. Our goals are to obtain quantitative and systems-wide global measurements, to perform dynamic serial measurements, and to integrate multiple and various data sets into models. Increasingly, our work has been focused in reconciling the gap that exists between imaging and traditional cell biology research, but in an in vivo setting. Our work on nanomaterials and the development of novel miniaturized nuclear magnetic resonance (µNMR) chips has led to advanced clinical trials. Whilst our research is primarily basic in nature, much of our work has a translational focus, with in vivo imaging playing a major role. Some specific research projects include:
Intracellular In-Vivo Imaging
New microscopic imaging technologies are being used to understand the complexity, heterogeneity and in vivo behavior of cancers. We are particularly interested in understanding the spatiotemporal activity of specific proteins (certain kinases and receptors), biological processes (apoptosis, proliferation) and cell-cell interactions in vivo. These experiments invariably use engineered cell lines and mouse models using a panoply of fluorescent reporter proteins. For example, we are asking questions like: how does the molecular machinery of signaling pathways interact in real time; what are the kinetics and flux rates of such networks; what are the differences between networks in malignant cells and normal tissues; can we exploit differences to make less toxic and more efficacious drugs; what are the "hubs" that will translate into most efficient read-outs of cancer development and therapeutic efficacy. Results from ongoing in vivo microscopy projects will likely have an impact on our understanding of tumor biology at the systems level, promote earlier clinical diagnosis and accelerate drug development.
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 developing in vivo imaging agents for 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. We typically first develop and test library of compounds and validate key hits by imaging by intravital microscopy. We also 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, we explore the translational potential of hits using the imaging probes. These are typically investigated in genetically engineered mouse models under combination therapy.
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.
Dr. Weissleder 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. His lab has been a driving force in studying human biology, especially cancer and inflammatory diseases. He has developed systematic ways to explore disease biology using in vivo imaging and has been instrumental in translating several discoveries into new drugs.