Pellecchia Laboratory Webpage

Maurizio Pellecchia, Ph.D.

Burnham Institute for
Medical Research

Research Focus
Dr. Pellecchia’s research focuses on the characterization of intermolecular interactions, on the determination of protein structures and on the development of small molecule inhibitors of protein targets involved in cell-signaling, virulence factors and host-pathogens interactions. The resulting compounds are then used as molecular probes to provide further understanding on the mechanism of action of their respective targets. The overall goal of the laboratory is to successfully bring together basic sciences involving modern nuclear magnetic resonance spectroscopy (NMR) techniques, computer modeling and traditional medicinal chemistry to elucidate the molecular basis of disease and to develop novel therapeutic compounds. Amongst the several projects that Dr. Pellecchia’s laboratory have initiated in the past years, noteworthy are the discovery, characterization and further development of potential therapeutic compounds targeting proteins of the Bcl-2 family, such as Bcl-xL and Bcl-2 (cancer targets) as well as Bid (involved in neurodegenerative diseases) and protein kinases such as p38 and Jnk (inflammation and diabetes). In addition, other very active areas of research involve the development of antitoxin compounds targeting the Anthrax metalloproteinase LF and protein components of the type-III secretion system, common to many pathogens, including Yersinia pestis and Salmonella. Finally, an area in which Dr. Pellecchia remains particularly interested is the development of novel NMR-based techniques to aid the characterization of protein structure, protein-protein and protein-ligand interactions using NMR spectroscopy. The design and synthesis of several high affinity ligands, for example, was made possible by the SAR by ILOEs approach, a NMR-based method developed in Dr. Pellecchia’s laboratory that enables the identification of high affinity ligands for a given protein target.

Biography
Dr. Pellecchia is a medicinal chemist with a strong background in biophysics and NMR-based drug design. He trained at the University of Naples (Italy) where he obtained his Ph.D. in Pharmaceutical Sciences, at the ETH-Zurich (working with 2002 Nobel Laureate Prof. Dr. Kurt Wüthrich) and the University of Michigan. Prior to his recruitment at The Burnham Institute as Associate Professor, Dr. Pellecchia spent a few years in the pharmaceutical industry. Dr. Pellecchia’s laboratory is centered on the characterization of intermolecular interactions, protein structure and on the development of small molecule inhibitors in systems involved in cell-signaling and apoptosis for the treatment of several human diseases including cancer, neurodegeneration and infectious diseases.

Tomas Mustelin, Ph.D.

Amgen Corporation

Research Focus
Dr. Mustelin investigates a family of genes called protein tyrosine phosphatase (PTPases), many of which act as tumor suppressors in numerous types of human cancer. It is anticipated that damage or loss of many additional family members will be found to underlay human disease, particularly cancers of white blood cells (e.g. leukemias and lymphomas). Dr. Mustelin has generated the tools to study some 35 different PTPases, representing nearly half of the genes in this family in the human genome. Dr. Mustelin's work aims at understanding the exact function of each of these PTPases in the cell's machinery for growth, survival, and death, in the white blood cell system. The results of Dr. Mustelin's research will help him and others to design rational approaches for the combat of cancer.

Biography
Tomas Mustelin earned his M.D. and Ph.D. degrees from University of Helsinki in 1987. He trained as a postdoctoral fellow at The Scripps Research Institute in La Jolla, 1988-1990. Dr. Mustelin returned to Finland for two years in clinical practice and research as a Junior Scientist with the Finnish Academy of Sciences at University of Helsinki. He was appointed Docent at University of Helsinki in 1992, an appointment he maintains to this day. From 1992-1998, Dr. Mustelin worked at La Jolla Institute of Allergy and Immunology in San Diego, as Assistant, then Associate Member. He was affiliated briefly with the Sidney Kimmel Cancer Center in San Diego prior to his recruitment to The Burnham Institute in September 1999.

Jeff Price, M.D.

Burnham Institute for
Medical Research

Research Focus
The central theme is the development of fully automated quantitative microscopy, or scanning cytometry, for biomedical applications. The instrumentation research areas include high performance autofocus, real-time image segmentation and image fluorometry. These are key components for a scanning cytometer capable of accurate, exhaustive analyses of the 100,000 – 10,000,000 cells on a single microscope slide at optical resolution (usually ≤ 0.5 x 0.5 mm2 pixels). Quantifying the measurement accuracy and/or precision of each step in the scanning cytometry process (e.g., autofocus followed by image segmentation, fluorometry and cell classification) are key components of the research. Current and proposed biomedical research areas include cervical (Pap smear) cancer screening, rare event detection (e.g., locating fetal cells in maternal circulation for genotyping), and chemotherapy testing using time-lapse scanning cytometry of living cells cultured on the microscope stage.

Biography
Jeffrey H. Price received his M.D. degree from Loma Linda University, Loma Linda, CA, in 1985, and his Ph.D. degree in bioengineering from the University of California, San Diego, in 1990, where he also received his postdoctoral training. In 1993, he was appointed Assistant Project Scientist and, in 1996, Associate Research Scientist. From 1994 to 2004 he directed the NSF-Whitaker Quantitative Imaging and Confocal Microscopy Resource in Bioengineering at UCSD. In 1999 he founded Q3DM, Inc., which marketed his research group’s high throughput microscopy inventions for cell-image-based screening, and which was purchased by Beckman Coulter, Inc. in 2003. In 2004 he Co-Founded Vala Sciences Inc, which develops and markets software and kits for cell-image based assays. He was recruited to the position of Associate Professor at The Burnham Institute in 2004, where he is a member of the Signal Transduction and Stem Cells and Regeneration Research Programs. With its collaborators, his laboratory is focused on automated analytical microscopy research for tissue proteomics, tracking of cell migration and differentiation, and rare cell diagnostics.

Mark Mercola, Ph.D.

Burnham Institute for
Medical Research

Research Focus
Research is directed at discovering molecules that promote differentiation of cardiomyocyte progenitors that will ultimately be useful for regeneration of muscle cells that are lost in heart disease. To do this, we 1) study heart formation during embryonic development to learn about the natural cell and tissue interactions that control heart formation, 2) study cardiomyocyte differentiation in mouse and human embryonic stem cells (ESCs), and 3) use robotic screening approaches to discover small molecules for cardiomyocyte production from ESCs.

Recent studies from the laboratory led to the discovery of signaling cascades that specify cardiogenic mesoderm in the early embryo and, subsequently, control the formation of certain cardiac tissues, such as heart muscle cells. Signaling cascades initiated by Wnt, BMP and Notch proteins are critical, as are complex interactions with tissues outside the heart field such as cells of the developing nervous system. Knowledge of the pathways that produce heart tissue in embryos is being applied to cardiomyogenesis for regenerative medicine applications.

A second emphasis of the lab focus is the production of pancreatic beta cells for diabetes applications. As for cardiomyocytes, the approach is to develop automated screening procedures to discover genes, proteins and small molecules that can be used to produce beta cells. Starting cell sources are ESCs as well as primary and immortalized human pancreatic cells.

Biography
Mark Mercola earned his Ph.D. from the University of California, Los Angeles in 1985. Dr. Mercola trained as a postdoctoral fellow at the Dana-Farber Cancer Institute and Department of Microbiology at Harvard Medical School in Boston, MA. He was appointed Assistant Professor in the Department of Cell Biology at Harvard Medical School in 1991 and Associate Professor in 1996. Dr. Mercola joined the Burnham Institute in 2002 where he is Professor in the Neurodegeneration and Aging Centerand is also an adjunct Professor in the Department of Pathology at the University of California, San Diego School of Medicine.

Ziwei Huang, Ph.D.

Burnham Institute for
Medical Research

Research Focus
Dr. Huang’s research focuses on both understanding the chemical basis of molecular recognition in protein-protein and protein-ligand complexes and translating such basic knowledge into the discovery of new drugs. By integrating the tools of structure-based drug design, synthetic chemistry, biophysical and biochemical analysis, and molecular and cellular biology, my primary interest is to generate novel chemical modulators of protein biological function and use them as small molecular probes to explore the structure-function relationship and molecular mechanism of biological processes involved in immunology and cancer cell biology. The second goal of my research is to further develop these molecular probes into new therapeutic agents for the treatment of cancer. One example is our focus on Bcl-2. Bcl-2 family proteins are key regulators of apoptosis or programmed cell death which is implicated in many human diseases including cancer and neurodegenerative disorder. My lab has shown that synthetic cell permeable Bcl-2 binding peptides can induce apoptosis of tumor cells and suppress the growth of tumor in mice. In addition, my group discovered, using computer screening techniques, organic compounds that mimic the tumor-killing effect of Bcl-2 binding peptides. These findings have demonstrated a novel approach of using chemical modulation of Bcl-2 function as an anti-cancer strategy. Our laboratory is planning further studies to advance these Bcl-2 inhibitors to human clinical trials as a new class of anti-cancer drugs.

Biography
Dr. Ziwei Huang received a Ph.D. in chemistry from the University of California at San Diego in 1993, working with Dr. Murray Goodman on biologically active peptides and peptide mimics. From 1993-1995, he undertook a two-year postdoctoral research at the University of California at San Francisco, working with Drs. Stanley Prusiner (1997 Nobel Laureate in Medicine) and Fred Cohen on structure of Prion protein and mechanism of Mad Cow Disease. In 1995, he became an Assistant Professor at the Kimmel Cancer Center of Jefferson Medical College in Philadelphia. In 2000, he joined the faculty of Biochemistry, Chemistry, and Biophysics at the University of Illinois at Urbana-Champaign as an Associate Professor with tenure. In 2004, Dr. Huang was recruited to San Diego as a Full Professor at the Burnham Institute and Adjunct Full Professor at School of Medicine of University of California at San Diego.

John Cashman, Ph.D.

Human BioMolecular
Research Institute

Director and Founder, has more than 23 years experience in biomedical research as a researcher, consultant, entrepreneur or administrator. In 1997, he founded the Human BioMolecular Research Institute, a non-profit research institute dedicated to performing fundamental and applied research to address important human diseases of the central nervous system. Previously, he was Senior Scientist at the Seattle Biomedical Research Institute and prior to that, he was Associate Director for the IGEN Research Institute in Seattle, Washington. In 1984, he was appointed Assistant Professor of Chemistry and Pharmaceutical Chemistry at the University of California, San Francisco. He completed a postdoctoral fellow in the Department of Chemistry at Harvard University in Cambridge, Massachusetts with Professor E.J. Corey (1982-1984). In 1990, Professor Corey received the Nobel Prize. Dr. Cashman received his Masters and doctorate degrees in Medicinal Chemistry from the University of Kansas, Lawrence, Kansas (1982). Prior to graduate school, he obtained bachelor degrees in chemistry and biology at the College of Creative Studies, University of California, Santa Barbara (1977). Dr. Cashman was a University of California Presidents Undergraduate Researcher (1974-1976), received a Sigma Xi Undergraduate Research fellowship (1975), was a PEW Scholar Nominee at the University of California, San Francisco (1986), received a March of Dimes Basil O’Connor Research Award (1986), was appointed Technical Advisor, San Francisco Estuary Project (1990) and was elected Fellow of the American Association for the Advancement of Science in 1996. In 1991, Dr. Cashman was appointed to the Editorial Advisory Board, Chemical Research in Toxicology and in 1999 he was appointed to the Editorial Advisory Board of Current Drug Metabolism. Dr. Cashman is the author of over 150 research articles or book chapters and 6 patents in the area of drug discovery and evaluation. He is extensively consulted by biotechnology, pharmaceutical industry and government in various areas of human drug development, drug safety evaluation, medicinal chemistry, pharmacogenetics and biochemical toxicology. Dr. Cashman is on the Board of Directors of three biotechnology companies.

Robert Abraham, Ph.D.

Wyeth Research

Robert Abraham earned his Ph.D. in Pharmacology from the University of Pittsburgh in 1981. He trained as a postdoctoral fellow in pharmacology and immunology at the Mayo Clinic and Mayo Foundation in Rochester, Minnesota, where he was promoted to Assistant Professor in 1986 and Associate Professor in 1992. In 1997, Dr. Abraham joined the Department of Pharmacology and Cancer Biology at Duke University Medical Center, where, in 1999, he was appointed Glaxo-Wellcome Professor of Molecular Cancer Biology. Dr. Abraham was recruited to the Burnham Institute for Medical Research in 2001 to found and direct the Institute's Signal Transduction Program. He served as Director of the Institute's NCI Cancer Center from 2002 - June, 2005, at which time he was recruited to Wyeth Laboratories to direct their cancer drug discovery program. Dr. Abraham maintains collaboration with the Burnham Institute for Medical Research as Adjunct Professor.

MDDT course 2007