Research

Dr. Weissleder is a Professor at Harvard Medical School, Director of the Center for Systems Biology at Massachusetts General Hospital (MGH), Director of the Center for Molecular Imaging Research, and Attending Clinician (Interventional Radiology) at MGH. Dr. Weissleder is also a member of the Dana Farber Harvard Cancer Center, the Harvard Stem Cell Institute (HSCI) leading its Imaging Program and an Associate Member of the Broad Institute (Chemical Biology 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 500 original publications in peer reviewed journals, over 80 review articles, has authored and co-authored several textbooks and holds 15 patents. Dr. Weissleder is currently the principal investigator of several RO1 NIH grants, a P50 Center grant, a U24 grant, and a UO1 consortium focusing on nanotechnology. He is a founding member of the Society for Molecular Imaging Research and served as its President in 2002. 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 and the Academy of Molecular Imaging 2006 Distinguished Basic Scientist Award.

Research Interests

One of the major research interests has been the development of novel molecular imaging tools to the study of complex human diseases. He has made fundamental discoveries in early disease detection, development of nanomaterials for sensing and systems analysis. His research has been translational and several of his developments have led to advanced clinical trials.

Research Projects

Nanoparticle libraries to identify novel ligands for interrogation of cellular pathways

Small molecules derived from diversity oriented synthesis (DOS) are commonly used as a discovery platform to identify new drugs, to approximate ligand/receptor binding kinetics and resultant hits have been used for system wide perturbations in cell based assays. This project uses nanoparticle platforms to immobilize DOS compounds to increase target avidity through multivalency, to create new chemical entities, to visualize biological interactions in vivo and to impart more optimal pharmacokinetics to small molecules. Based on our prior work with novel (magneto)fluorescent nanoparticles, we have begun to test different library methods and differentially screen thousands of molecules against known (and unknown) biological targets. The library methods employed include chemical ones (DOS compounds, natural compounds, approved drugs, curated small molecule collections, peptide libraries and aptamer libraries) and biological ones (phage display, mRNA display, SELEX, Bacterial display, ribosomal display, cell display, covalent DNA display, yeast 2 hybrid, sh/si RNA). These methods and materials will facilitate the development of functional nanomaterials for applications such as differentiating cell lines, detecting distinct cellular states and targeting specific cell types.

Identification of key genes and gene function involved in complex human diseases

Genomic profiling has identified large data sets on many complex diseases in the mouse and humans. However, the variability of such data sets, importance of network nodes and clinically imageable targets are much more difficult to discern. This project uses diverse data mining tools as well as network analyses to identify novel targets for specific cancer types, Type 1 diabetes and atherosclerosis. A second complementary approach has been the use of in vivo library displays to identify "hits" and then discern the cellular binding partner. Using these methods we are currently working on several unique leads including cell surface proteases.

Development of novel miniaturized sensing technologies (chips) for real-time high-throughput analysis

Multiplexed, platform independent and rapid analysis of biological specimen remains a major bottleneck in unraveling complex biological phenomena. A number of established techniques provide accurate measurements, facilitate early disease detection and have been used to gain valuable insights into biology at the systems level. However, many of the techniques rely on extensive and time consuming purification of samples, typically followed by a set of amplification strategies and often do not allow rapid multiplexed measurements required in complex diseases. We have recently developed a chip based micro-NMR (µNMR) system to perform highly sensitive measurements in complex biological samples. NMR devices allow measurements in turbid samples, characterization of chemical species and form the basis of clinical imaging systems. Using microfabrication technology we miniaturized elements of an NMR system to perform proton T2 measurements of aqueous biological samples. Using readily available magnetic nanoparticles as sensors for proximity assays the technique allows parallel measurements of nucleic acids, proteins, peptides, metabolites and cells. Importantly, the spatial proximity of two nanoparticles by an analyte of choice results in large-scale amplification allowing rapid, parallel detection of biological targets in unprocessed samples. The integration of the sensor with microfluidic system allows facile control and manipulation of small volumes of liquid, and additional magnetic separation and concentration of targets from a complex parent specimen. In this project we apply the chip for parallel measurements of cellular proteins.

Selected References

Lee H, Sun EY, Ham DH, Weissleder. Chip-based sesnor for molecular analysis of cells. Nature Medicine, 2008, in press

Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007;445: 661-5.

Weissleder R. Molecular Imaging in Cancer. Science. 2006;312: 1168-1171.

Bardeesy N, Aguirre AJ, Chu GC, Cheng KH, Lopez LV, Hezel AF, Feng B, Brennan C, Weissleder R, Mahmood U, Hanahan D, Redston MS, Chin L, Depinho RA. Both p16Ink4a and the p19Arf-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc Natl Acad Sci. 2006;  ePub.

Binstadt BA, Patel PR, Alencar H, Nigrovic PA, Lee DM, Mahmood U, Weissleder R, Mathis D, Benoist C. Particularities of the vasculature can promote the organ specificity of autoimmune attack. Nature Immunology. 2006;7(3): 284-92.

Rabin O, Manuel Perez J, Grimm J, Wojtkiewicz G, Weissleder R. An X-ray computed tomography imaging agent based on long-circulating bismuth sulphide nanoparticles. Nature Materials. 2006;5(2): 118-22.

Weissleder R, Kelly K, Sun E, Shtatland T, Josephson L. Cell-specific targeting of nanoparticles by multivalent attachment of small molecules. Nature Biotechnology. 2005;23: 1418-1423.

Zacharakis G, Kambara H, Shih H, Ripoll J, Grimm J, Saeki Y, Weissleder R, Ntziachristos V. Volumetric tomography of fluorescent proteins through small animals in vivo. Proc Natl Acad Sci. 2005;102: 18252-18257.

Grimm J, Kirsch DG, Windsor SD, Kim CF, Santiago PM, Ntziachristos V, Jacks T, Weissleder R. Use of gene expression profiling to direct in vivo molecular imaging of lung cancer Proc Natl Acad Sci. 2005;102(40): 14404-14409.

Ntziachristos V, Ripoll J, Wang L, Weissleder R Looking and Listening to light: the evolution of whole-body photonic imaging. Nature Biotechnology, 23: 313-320 , 2005.

Shah K, Bureau E, Kim DE, Yang K, Tang Y, Weissleder R, Breakefield XO. Glioma therapy and real-time imaging of neural precursor cell migration and tumor regression. Annals of Neurology, 57(1): 34-41 , 2005

Ntziachristos V, Schellenberger EA, Ripoll J, Yessayan D, Graves E, Bogdanov A Jr, Josephson L, Weissleder R. Visualization of antitumor treatment by means of fluorescence molecular tomography with an annexin V-Cy5.5 conjugate. Proc Natl Acad Sci, 101(33): 12294-9 , 2004.

Chen ML, Pittet MJ, Gorelik L, Flavell RA, Weissleder R, von Boehmer H, Khazaie K. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-{beta} signals in vivo. Proc Natl Acad Sci, 102(2): 419-24 , 2004.

Denis M, Mahmood U, Benoist C, Mathis D, Weissleder R. Imaging Inflammation of the Pancreatic Islets in Type 1 Diabetes. Proc Nat Acad Sci, 2004; 101: 1263412639.

Tang Y, Kim M, Carrasco D, Kung AL, Chin L, Weissleder R. In vivo assessment of RAS-dependent maintenance of tumor angiogenesis by real-time magnetic resonance imaging Cancer Research. 2005;65(18): 8324-30.

Grimm, J., Perez, J. M., Josephson, L., and Weissleder, R. Novel nanosensors for rapid analysis of telomerase activity. Cancer Research, 64: 639-43 , 2004.

Harisinghani M, Barentsz J, Hahn PF, Deserno WM, Tabatabaei S, Hulsbergen-va de Kaa C, de la Rosette J, Weissleder R. Noninvasive detection of clinically occult lymph node metastases in prostate cancer. New England Journal of Medicine, 2003; 348;2491-2499.

Weissleder R, Ntziachristos V. Shedding light onto live molecular targets. Nature Medicine, 2003; 9:123-128.

Perez JM, Josephson L, O’Loughlin T, Hogemann D, Weissleder R. Magnetic relaxation switches capable of sensing molecular interactions. Nature Biotechnology, 2002; 20:816-820.

Ntziachristos V, Tung C, Bremer C, Weissleder R. Fluorescence mediated tomographic imaging system. Nature Medicine 2002; 8:757-760.

Weissleder R. Scaling down imaging: molecular mapping of cancer in mice. Nature Cancer Review, 2002, 2:1-10

Bremer C, Tung CH, Weissleder R. In vivo molecular target assessment of MMP-2 inhibition. Nature Medicine, 2001; 7:743-748.

Weissleder R, Moore A, Mahmood U, Bhorade R, Benveniste H, Chiocca A, Basilion J. High resolution in vivo imaging of transgene expression. Nature Medicine; 2000, 6:351-355.

Josephson L, Perez JM, Weissleder R. Magnetic nanosensors for the detection of oligonucleotide sequences. Angewandte Chemie, 2001; 40:3204-3206.

Lewin M, Carlesso N, Tung C, Tang X, Cory D, Scadden D, Weissleder R. Tat peptide derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nature Biotech, 2000;18:410-414