The Biochemistry and Biophysics Center carries out research that brings chemical and physical approaches to the study of biological problems. The principal investigators of the Center focus on topics that range from DNA transcription to cellular degeneration. To understand the mechanisms involved in these diverse processes, the investigators develop instruments and techniques to resolve, quantify, model, manipulate, and simulate biological mechanisms at molecular and cellular levels. The focus of Center research is to develop both experimental and theoretical models of biomolecular structure, and use these models to discover the link between the structure, function, and regulation of biologically active molecules and processes. This basic research helps fuel scientific discovery that may one day help advance research related to heart, lung, blood, and sleep conditions or other fields.
Visualizing the workings of living cells has transformed biological understanding. Today, optical technologies allow us to detect the movements of macromolecules in cells embedded within living tissues, but there is still a need to improve resolution, speed, and minimize tissue damage. The Laboratory of Advanced Microscopy and Biophotonics, led by Dr. Jay R. Knutson, uses optical physics and fluorescence to create better instruments for examining the inner workings of cells and the macromolecular (proteins, lipids, and DNA) complexes within.
The enzymatic activity of many proteins is regulated by certain chemical modifications. Research in the Laboratory of Biochemical Dynamics involves understanding biochemical mechanisms of enzyme action and cellular regulation with a focus on the regulatory roles of reversible protein modifications. Led by Dr. P. Boon Chock, the lab is also interested in free radicals and reactive oxygen species-mediated oxidative modification of proteins and RNA. Dr. Chock’s work revealed the advantages of reversible modification cascades in cell signaling in view of their enormous potential for signal and rate amplification and regulatory flexibility. Dr. Chock also showed the role of protein glutathionylation in regulating the activity of tyrosine phosphatase 1B and 2-Cys-peroxiredoxin, in growth factor-mediated actin polymerization, and in translocation.
Because eukaryotic cells depend on molecular oxygen for normal metabolism, they generate reactive oxygen species (ROS) that can cause multiple forms of cellular stress and damage. For several years, the Laboratory of Biochemistry, led by Dr. Rodney L. Levine, has focused its research on the identification of oxidative modifications of proteins. Dr. Levine is interested in the conditions that give rise to modifications in which amino acids are modified, and the impact those modifications have on enzymatic function or structural integrity. Dr. Levine is pursuing the hypothesis that oxidative modifications of proteins are not always a negative effect of stress, but also participate in normal cellular signaling.
The Laboratory of Bioseparation Technology’s primary interest is in inventing methods of isolating, purifying, or analyzing materials of biomedical interest—including cells, macromolecules, and small molecular weight compounds—by means of counter-current chromatography and elutriation. This lab is led by Dr. Yoichiro Ito, who has helped develop innovative separation methods, including the coil planet centrifuge for blood cells, and a novel rotary seal-free centrifuge device for blood that limits the damage to platelets caused by the commonly used rotary seal.
The Computational Biophysics Section of the Laboratory of Computational Biology is a group of researchers, led by Dr. Bernard Brooks, who use high-performance computing and macromolecular simulation to investigate problems in biophysics and chemistry. Their research efforts involve the development of new methods to assist the interpretation of experiments for calculating binding free energies and partition coefficients, including those with pKa changes; for integrating multiple computational models into a multiscale computation; for new enhanced sampling methods and normal mode techniques; and for techniques for finding reaction pathways in complex systems. These developments are integrated into CHARMM and several other macromolecular simulation and quantum mechanical software packages, providing a complete set of tools for complementing and enhancing experimental research.
Whether through ultrasound, magnetic resonance imaging (MRI), or x-ray imaging, the ability to peer noninvasively into the human body has been an enormous boon to medicine. New technological advances provide an expanding horizon of better diagnostics through imaging. In the Imaging Physics Laboratory, led by Dr. Han Wen, the primary research focus is the development of biomedical imaging technologies. He applies physics discoveries to engineer novel solutions to challenges in medical imaging. He created imaging methods of body electrical properties, which grew into new fields of research. He also developed clinical MRI technologies. In x-ray imaging, he focuses on improving the information available in medical x-ray exams. X-ray imaging is robust and adaptable to almost any environment, but the use of ionizing radiation can pose health risks. Dr. Wen’s laboratory works on technologies to enrich the information from x-ray scans while reducing the doses to safer levels.
Magnetic resonance imaging (MRI) is an established medical imaging modality, providing unparalleled soft tissue contrast combined with good spatial resolution. MRI also has the potential to provide more than just anatomical imaging, e.g. image guidance for interventional procedures, multidimensional information and tissue characterization. The MRI Technology program, led by Adrienne Campbell-Washburn, is focused on the development of advanced cardiovascular MRI techniques, leveraging modern acquisition and reconstruction techniques, as well as state-of-the-art computational resources (GPUs and cloud computing) in the clinical environment. Specifically, the aim is to improve imaging speed, imaging for MRI-guided interventions, motion robustness, quantification, and clinical workflow.
The Laboratory of Membrane Biophysics applies information collected from computer simulations and statistical mechanics to biophysics, with an emphasis on cell membranes. Cell membranes are not only the physical barriers that partition cells into units with discrete sub-compartments; they are also dynamic, heterogeneous structures comprising multiple types of fats, proteins, and sugars which allow the cell to communicate with its environment. Led by Dr. Richard Pastor, the lab is combining experiments on simplified membranes with the fundamental principles and simulation techniques of physics to understand and model cell membranes on the atomic level. Such simulations hold extraordinary promise: in applied areas such as drug design, they could provide a detailed picture of drug binding and transport through the membrane; on a fundamental level, they could answer questions concerning cell fusion and signal transduction, and they are a valuable complement to experimental manipulations.
Membranes divide cells into compartments that are specialized for different functions; thus the membrane transport is vital for cells to exchange substances across the membranes in a tightly regulated way. Dysfunctions associated with the membrane transport may lead to adverse effects or disease. The Laboratory of Membrane Proteins and Structural Biology, led by Dr. Jiansen Jiang, focuses on two questions concerning the membrane transport. (1) How do the channels or transporters select their substrate molecules or ions? (2) How are the substrates moved across the channels or transporters? The lab uses a combination of cryo electron microscopy (cryoEM) and other tools to seek answers to these questions, while also working on method development to expand applications of cryoEM on life sciences research.
Every living cell ingests and secretes material by recycling parts of its membrane to form vesicles that are internalized (endocytosis) or externalized (exocytosis). These processes are broadly important and carefully regulated in all cell types, but in electrically active cells like neurons, they form the basis for rapid intercellular communication (synaptic transmission) and are therefore under precise temporal control. Dysfunctions in synaptic transmission contribute to several neurologic disorders. The Laboratory of Molecular and Cellular Imaging, led by Dr. Justin Taraska, studies how vesicles fuse with and are recaptured from the cell surface in excitable cells. Dr. Taraska seeks to identify the proteins that control these processes and determine their impact on human health and disease.
The Laboratory of Protein Conformation and Dynamics integrates complementary biophysical and biochemical techniques to understand the molecular mechanisms of amyloid formation. Aggregation of proteins into amyloid structures is a hallmark of human diseases such as Alzheimer’s disease and Parkinson’s disease. Interestingly, amyloid fibrils can also serve essential biological roles in organisms ranging from bacteria to humans. Moreover, many polypeptides with diverse amino acid sequences and folded states can form amyloid in vitro, implying common underlying features. Led by Dr. Jennifer C. Lee, research efforts focus on studying changes in protein conformation and interactions important for the mechanisms by which amyloid structures assemble under normal and pathological conditions. Through the development of instrumentation and new methodology, Dr. Lee strives to discover therapeutic agents and disease intervention approaches.
The fates and functions of RNA molecules in a cell are manifold. They may be translated, degraded, or in the case of retroviral RNA, even reverse transcribed into DNA and integrated into the genome. The Laboratory of Ribonucleoprotein Biochemistry, led by Dr. J. Robert Hogg, studies how RNAs attain unique functions in the cell by their intimate associations with proteins as part of ribonucleoprotein complexes (RNPs). In particular, Dr. Hogg’s focus has been on quality control and RNA surveillance: How does a cell distinguish and respond to faulty RNAs, whether produced internally or introduced virally? Dr. Hogg’s goal is to dissect mechanisms of RNP assembly and understand how particular RNA-protein interactions determine mRNA function and decay.
The Laboratory of RNA Biophysics and Cellular Physiology studies RNA molecules in their many guises. Led by Dr. Adrian R. Ferré-D’Amaré, the lab employs fundamental biophysical approaches to understanding the function of non-coding RNAs, and seeks to leverage this knowledge for the development of new therapeutics and biotechnological tools. The lab has a long-standing interest in examining how RNA molecules can adopt three-dimensional folds, whose complexity rivals those of proteins, and how their architectures enable non-coding RNAs to perform catalysis, recognize cellular metabolites and macromolecules (including proteins and other RNAs), and regulate gene expression. More recently, the lab has engaged in structural characterization and design of fluorescent RNAs. These molecules, RNA analogues of green fluorescent protein (GFP), can be deployed in live cells to study expression, traffic, localization and turnover of non-coding RNAs.
Enzyme mechanisms have traditionally been studied in biochemical and structural experiments that involve millions to billions of molecules. Enzymes, however, are complex molecular machines that, when subjected to individual scrutiny, reveal features that cannot be understood when studying in larger quantities. Single-molecule visualization and manipulation techniques are at the technological forefront of biological enquiry. In the Laboratory of Single Molecule Biophysics, led by Dr. Keir C. Neuman, these techniques—including optical and magnetic tweezers and fluorescence imaging, in combination with conventional molecular biology approaches—are employed to answer fundamental questions concerning enzyme function and regulation. Dr. Neuman’s research program is underpinned by single-molecule instrumentation that his laboratory designs and builds to elucidate enzyme mechanisms at the molecular level.
Nuclear magnetic resonance (NMR) spectroscopy is a powerful tool to probe biomolecular structures in solution. However, NMR cannot provide a direct image of the structures themselves; rather it generates a large number of signals characterizing the atomic interactions within a structure that are then used to computationally determine a structure to account for those interactions. The Laboratory of Structural Biophysics, led by Dr. Nico Tjandra, focuses on the basic physical chemistry that can be captured by NMR in order to answer questions about biomolecular interactions. In particular, Dr. Tjandra wants to improve the ability of NMR to study protein complexes in their proper context that is as part of multi-component systems in complex lipid environments.
The Theoretical Molecular Biophysics Laboratory, led by Dr. José Faraldo-Gómez, investigates how the biological activity of membrane proteins emerges from their structure, dynamics and environment. Membrane proteins mediate numerous essential processes in living organisms, such as the communication between and within cells and the uptake and metabolism of nutrients. Consequently, many health disorders in humans, from heart disease to neurodegeneration, are associated with the malfunction of these systems. Membrane proteins are also crucial for the survival of multi-drug resistant bacteria and tumor cells and are therefore potential targets against infection and cancer. The group uses high-end computer-simulation approaches and other theoretical methods, in synergy with experimental work. The premise of this research is that a detailed understanding of the molecular mechanisms of these systems will eventually foster the development of more effective pharmacological approaches.