University of California
675 Nelson Rising Lane, 3rd Floor
San Francisco, CA 94158
University of California
Research in the Glabe lab focuses on the structure, aggregation and mechanisms of pathogenesis of amyloids in degenerative diseases. The main research programs center on the production of conformation dependent antibodies that specifically recognize distinct assembly states of amyloids, the use of these antibodies in dissecting the pathogenic mechanisms of amyloids and their applications in vaccine development. Other areas of interest include the mechanism of membrane permeabilization by amyloid oligomers. Dr. Glabe and his colleagues have discovered that fibrils and prefibrillar oligomers represent alternative aggregation pathways for many different types of amyloids and that they have distinct underlying structural motifs that are generic to the particular aggregation state and are recognized by specific conformation dependent antibodies. The prefibrillar oligomer antibody recognizes the oligomeric conformation of all amyloids tested and not the native conformation, random coil monomer or fibrillar amyloids regardless of protein sequence. We found that this antibody neutralizes the toxicity of amyloid oligomers in vitro and that vaccination of transgenic mouse models against the prefibrillar oligomers prevents amyloid deposition and cognitive dysfunction. The fibril specific antibody recognizes fibrils and soluble fibrillar oligomers of many different types of amyloids, but not prefibrillar oligomers, monomer or natively folded proteins. This indicates that fibrils have a generic structure that is distinct from that of prefibrillar oligomers, implying that they may have distinct toxic mechanisms. These discoveries indicate that amyloids share common structures and imply that they also share a common primary mechanism of amyloid oligomer pathogenesis. This suggests that therapies that specifically target these common structures may be effective for many different types of amyloid related degenerative diseases. Current work is focused on characterizing the detailed structures of these aggregation states and the common mechanisms of toxicity, which may involve the permeabilization of cellular membranes by prefibrillar oligomers.
Professor David E. Wemmer did undergraduate work at UC Davis, majoring in Mathematics and Chemistry (BS 1974), and then moved to UC Berkeley for graduate school where he joined Alex Pines' lab and worked on high resolution solid state NMR and multiple quantum NMR. After some initial studies using lineshape analysis to probe dynamics in molecular crystals, the focus shifted to developing and applying multiple quantum NMR methods (PhD 1979).
After spending a year with Prof. Michael Mehring in the Physics Department at the University of Dortmund (Germany), continuing work in spectroscopic methods for solid state NMR he joined the Stanford Magnetic Resonance Lab and began to apply NMR in biological systems, and also did some in vivo NMR work. After three years at Stanford a move to the University of Washington where the focus was using NMR to study DNA structure and ligand interactions. In 1985 he returned to Berkeley on the faculty, was promoted to Associate Professor 1990, then Professor in 1992. From 1992-1996 he also served as Assistant Dean in the College of Chemistry.
Prof. Wemmer’s research program continues to exploit NMR spectroscopy for studies of biological systems, but in recent years crystallography and other approaches are playing increasing roles. Over the years his lab has done been many different studies of DNA-ligand interactions, that included development of a design for sequence specifically targeted minor groove binding compounds, as well as studies of covalent adducts. Protein structure work has mostly been in the areas of transcription factors, other nucleic acid binding proteins and bacterial transcriptional activators. There have also been collaborations with his PhD mentor Pines in the area of solid state NMR of amyloidogenic proteins, and recently on the use of hyperpolarized 129Xe NMR for probing biological systems.
Jeffrey A. Reimer is the Warren and Katharine Schlinger Distinguished Professor and Chair of the Department of Chemical Engineering at the University of California at Berkeley, and a faculty scientist at the E.O. Lawrence Berkeley National Laboratory. From 2000 to 2005 he was an Associate Dean in the UC Berkeley Graduate Division where his responsibilities included the assessment of doctoral programs. In 1998 he won the Donald Sterling Noyce Prize for Excellence in Undergraduate Teaching in the Physical Sciences and was given the AIChE Northern California Section Award for Chemical Engineering Excellence in Academic Teaching. In 2000 he was awarded the Chemical Engineering Departmental Outstanding Teaching Award. Professor Reimer was awarded the Distinguished Teaching Award in 2003, the highest award bestowed on faculty for their teaching.
Professor Reimer received his bachelor’s degree (with honors) from the University of California at Santa Barbara, and obtained his doctorate from the California Institute of Technology in 1980. Prior to his appointment at Berkeley in 1982, he was a postdoctoral fellow at IBM Research in Yorktown Heights, New York. At Berkeley he received the Presidential Young Investigator Award in 1985, and was named a Camille and Henry Dreyfus Teacher-Scholar in 1987. In 2002 he was named the R.W. Vaughan Lecturer at the Rocky Mountain Conference on Analytical Chemistry and Applied Spectroscopy, in recognition for his numerous contributions in the field of magnetic resonance spectroscopy. Professor Reimer was named a Mercator Professor of the Deutsche Forschungsgemeinschaft (DFG) at RWTH Aachen University in 2006. He was elected a Fellow of the American Association for the Advancement of Science for “contributions to understanding materials chemistry though the application of sophisticated spectroscopic and physical measurements.”
The goal of Professor Reimer's research is the exploration of spectroscopic methods that inform society about materials chemistry and analyses.
Alexander Pines is the Glenn T. Seaborg Professor of Chemistry at the University of California, Berkeley; Senior Scientist, Materials Sciences Division Lawrence Berkeley National Laboratory; and Faculty Affiliate of QB3, the California Institute for Quantitative Biomedical Research. He obtained his PhD in Chemical Physics at MIT and joined the faculty at Berkeley in 1972. Among his numerous honors, Pines was awarded the 1991 Wolf Prize for Chemistry, the Langmuir Award of the American Chemical Society and the Faraday Medal of the Royal Society UK. He is a member of the US National Academy of Sciences, a Foreign Member of the Royal Society and a Governor of the Weizmann Institute of Science in Israel. A renowned educator, Pines has been recognized by the University of California’s Distinguished Teaching Award, and has been mentor to generations of graduate students and postdoctoral fellows, the self-dubbed "Pinenuts," many of whom who hold leading positions worldwide.
Pines is a pioneer in the development of nuclear magnetic resonance (NMR) spectroscopy, particularly for solids. His program addresses the establishment of new concepts and techniques in NMR and magnetic resonance imaging (MRI), in order to enhance their capability and extend their applicability for the investigation of molecular structure and organization in systems from materials to organisms. The study and diagnostic use of quantum spins interacting with each other and with other degrees of freedom require an understanding of quantum coherence and decoherence and the development of new theoretical and experimental methods, one outcome of which is the establishment of new methodologies and the accompanying design and fabrication of novel, next-generation NMR and MRI instrumentation. His innovations include contributions to multiple-pulse coherent averaging, time-reversal of dipolar couplings, cross-polarization and high resolution carbon-13 NMR, multiple-quantum coherence, multidimensional spectroscopy, zero-field NMR, and ideas and methods for novel sample spinning and correlation.
Professor Jeffrey R. Long is Professor of Chemistry at the University of California, Berkeley and Faculty Senior Scientist in the Materials Sciences Division at Lawrence Berkeley National Laboratory. In addition, he is lead-PI for the Berkeley Hydrogen Storage Program and Deputy Director of the Berkeley Center for Gas Separations. With over 100 publications, his research areas include the synthesis of inorganic clusters and solids with unusual electronic and magnetic properties, generation of microporous metal-organic frameworks for applications in hydrogen storage and carbon dioxide capture, and the development of molecular catalysts for electro- and photochemical water splitting. His scientific contributions have resulted in a number of awards, including the NSF Special Creativity Award (2003-2005 and 2009-2011) and the National Fresenius Award (2004).
Chair, Division of Community Health & Human Development
William Jagust’s lab is engaged in the study of brain aging and dementia. They use the techniques of positron emission tomography (PET), structural magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), neuropsychology and cognitive neuroscience to understand the anatomic, biochemical and neurochemical bases of changes in behavior with age and dementia.
Professor, Department of Pharmaceutical Chemistry
Dr. Wells received a BA degree in biochemistry from the University of California, Berkeley, and a PhD degree in biochemistry from Washington State University. His postdoctoral studies were done at Stanford University Medical School, Department of Biochemistry. Dr. Wells was the founding member of the Protein Engineering Department at Genentech, Inc where he worked for 16 years. His research focused on designing new functional properties into enzymes and hormones and developing new technologies for engineering proteins. In 1998, Dr. Wells founded Sunesis Pharmaceuticals where he served as President and Chief Scientific Officer and developed a novel fragment discovery technology known as disulfide trapping or Tethering. In 2005, Dr. Wells joined UCSF as the Harry W. and Diana Hind Distinguished Professor in Pharmaceutical Sciences. He is a joint Professor in the Departments of Cellular & Molecular Pharmacology, and Pharmaceutical Chemistry.
We are interested in the discovery and design of small molecules that trigger or modulate cellular processes in inflammation and cancer. Our research spans the multiple disciplines of biophysics, cell biology, molecular biology, biochemistry and chemistry. We are interested in the allosteric “circuitry” in proteins, i.e., how two distant functional sites communicate through a protein. In particular, we are focused on the signaling circuitry in pathways involved in cell death and cellular inflammation. We are developing specific cell active enzyme inhibitors or activators by using a novel disulfide trapping technology which allows us to target specific sites on proteins and determine their role in driving cellular signaling processes. This technology allows us to trap allosteric states so that they may be studied by biophysical and mutational means. We are using this approach to determine the role of specific inflammatory caspases via selective inhibitors and study activation of proteins in proliferation and apoptotic pathways via allosteric activators. This approach will identify “orphan allosteric sites’ which may have natural binding partners and pose new targets for drug discovery. In addition, we are developing methods for tagging N-termini of proteins using engineered enzymes so we can follow proteolytic cascades especially those in apoptosis and cellular inflammation.
Howard Hughes Investigator, Department of Cellular & Molecular Pharmacology
To ensure proper folding, cells have evolved a sophisticated and essential machinery of proteins called molecular chaperones that assists the folding of newly made polypeptides and disposes of misfolded proteins. The importance of proper protein folding is underscored by the fact that a number of diseases, including Alzheimer's and those involving infectious proteins (prions), result from protein-misfolding events. My research focuses on identifying and understanding the machinery necessary for efficient folding, as well as studying the mechanism and consequences of protein misfolding especially as it relates to prion-based inheritance. We are also developing experimental and analytical approaches for exploring the organizational principles of complex biological systems as well as tools for globally monitoring protein translation with sub-codon resolution.
Dr. Laurence Tecott's laboratory uses molecular genetic approaches to examine the contributions of serotonin (5-HT) receptors to the actions of neuropsychiatric drugs and to the genetic determination of complex behavioral traits. For example, the serotonergic control of feeding is being examined in studies of 5-HT receptor mutant mice. Animals lacking the 5-HT2C receptor subtype display chronically elevated food intake, leading to "middle-age" obesity and type 2 diabetes mellitus.
These mice display reduced sensitivity to the appetite suppressant fenfluramine, further implicating this receptor as a target for antiobesity drug development. The genetic control of neural systems underlying anxiety and depression is another focus of investigation. Animals devoid of 5-HT1A receptors exhibit enhanced anxiety-like responses in a variety of behavioral assays and robust antidepressant-like responses in an animal model of depression. These animals exhibit markedly enhanced sensitivity to the effects of antidepressants such as fluoxetine (Prozac).
Recent advances in gene targeting and gene expression technologies will facilitate studies of the mechanisms through which serotonin receptors modulate behavior and the actions of neuropsychiatric drugs.