James A. Wells | |
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Born | April 28, 1950 |
Nationality | American |
Education | University of California, Berkeley (B.A., 1973), Washington State University (Ph.D., 1979) |
Known for | Protein Engineering |
Spouse | Carol A Windsor |
Children | Julian James Windsor-Wells, Natalie Hope Windsor-Wells |
Awards | National Academy of Sciences |
Scientific career | |
Fields | Chemical biology, protein engineering |
Institutions | University of California, San Francisco, Genentech, Inc., Sunesis Pharmaceuticals |
James Allen Wells (born April 28, 1950) is a Professor of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology at the University of California, San Francisco (UCSF) [1] and a member of the National Academy of Sciences. He received his B.A. degrees in biochemistry and psychology from University of California, Berkeley in 1973 and a PhD in biochemistry from Washington State University with Ralph Yount, PhD in 1979. He completed his postdoctoral studies at Stanford University School of Medicine with George Stark in 1982. He is a pioneer in protein engineering, phage display, fragment-based lead discovery, cellular apoptosis, and the cell surface proteome.
Jim Wells began his independent research career as a co-founding member of the Protein Engineering Department at Genentech. At Genentech, Wells and his group pioneered "gain-of-function engineering" of enzymes (such as subtilisin [2] ), growth factors (human growth hormone [3] ), and antibodies by site-directed mutagenesis [4] and protein phage display. [5] [6] Several biologic products derived directly from these efforts ranging from Pegvisomat (Somavert) an engineered growth hormone antagonist for treatment of acromegaly, humanization of the Bevacizumab (Avastin) a VEGF antagonist for treating cancers, and engineered proteases developed for popular laundry detergents by Genencor International. His group developed fundamental technologies (cassette mutagenesis, alanine scanning, protein phage display) and protein design principles ("hot-spots" in protein interfaces, [7] additivity of mutational effects, receptor oligomerization in cytokines) commonly used for engineering enzymes, hormones, antibodies, and protein-protein interfaces. With Tony Kosssiakoff and Bart DeVos, they discovered the activation/dimerization mechanism of human growth hormone, a paradigm for cytokine signaling. [8] [9]
In 1998, Wells co-founded Sunesis Pharmaceuticals where he was CSO, and president. At Sunesis, the group developed a novel technology for site-directed fragment-based drug discovery, Tethering, [10] [11] and applied it to cancer and inflammation targets. They were among the first to develop potent small molecules to protein protein interfaces and cryptic allosteric sites considered undruggable. [12] Several of the compounds discovered at Sunesis are now in clinical development. They also discovered the anti-inflammatory drug Lifitegrast, which was subsequently developed by SarCODE [13] and is now sold by Shire for dry eye syndrome.
In 2005, Wells joined the faculty of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology at UCSF. He founded the Small Molecule Discovery Center and served as Chair of Pharmaceutical Chemistry for 8 years. His own lab initially focused on the molecular basis of cell death as applied to cancer and inflammation through elaborating native substrates of caspases. His team designed a suite of engineered enzymes for dissecting protease signaling pathways (subtiligase [14] and the SNIPer [15] ), E3 ligase substrates (the NEDDylator [16] ), a split-Cas9 [17] for temporal editing, and allosteric inhibitors, split-kinases [18] and new phosphospecific antibodies [19] [20] for probing protein phosphorylation pathways. In 2012, Wells founded the Antibiome Center [21] as part of the Recombinant Antibody Network, [22] devoted to generating human recombinant antibodies at a proteome-wide scale using high throughput platforms for antibody phage display. The Wells Lab now investigates how cell surface proteomes change in health and disease by applying mass spectrometry and protein and antibody engineering, to understand and disrupt human-disease-associated signaling processes. [23] [24] Several notable antibody technologies have also been developed including site specific methionine conjugation using redox-activated chemical tagging (ReACT), [25] antibody-based chemically induced dimerizers (AbCID), [26] antibody-Based PROTACs (AbTAC), [27] antibody targeting a proteolytic neoepitope, [28] and cytokine receptor-targeting chimeras (kineTAC). [29]
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events. Most commonly, protein phosphorylation is catalyzed by protein kinases, ultimately resulting in a cellular response. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used. The changes elicited by ligand binding in a receptor give rise to a biochemical cascade, which is a chain of biochemical events known as a signaling pathway.
A biosensor is an analytical device, used for the detection of a chemical substance, that combines a biological component with a physicochemical detector. The sensitive biological element, e.g. tissue, microorganisms, organelles, cell receptors, enzymes, antibodies, nucleic acids, etc., is a biologically derived material or biomimetic component that interacts with, binds with, or recognizes the analyte under study. The biologically sensitive elements can also be created by biological engineering. The transducer or the detector element, which transforms one signal into another one, works in a physicochemical way: optical, piezoelectric, electrochemical, electrochemiluminescence etc., resulting from the interaction of the analyte with the biological element, to easily measure and quantify. The biosensor reader device connects with the associated electronics or signal processors that are primarily responsible for the display of the results in a user-friendly way. This sometimes accounts for the most expensive part of the sensor device, however it is possible to generate a user friendly display that includes transducer and sensitive element. The readers are usually custom-designed and manufactured to suit the different working principles of biosensors.
Phage display is a laboratory technique for the study of protein–protein, protein–peptide, and protein–DNA interactions that uses bacteriophages to connect proteins with the genetic information that encodes them. In this technique, a gene encoding a protein of interest is inserted into a phage coat protein gene, causing the phage to "display" the protein on its outside while containing the gene for the protein on its inside, resulting in a connection between genotype and phenotype. These displaying phages can then be screened against other proteins, peptides or DNA sequences, in order to detect interaction between the displayed protein and those other molecules. In this way, large libraries of proteins can be screened and amplified in a process called in vitro selection, which is analogous to natural selection.
A single-chain variable fragment (scFv) is not actually a fragment of an antibody, but instead is a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of immunoglobulins, connected with a short linker peptide of ten to about 25 amino acids. The linker is usually rich in glycine for flexibility, as well as serine or threonine for solubility, and can either connect the N-terminus of the VH with the C-terminus of the VL, or vice versa. This protein retains the specificity of the original immunoglobulin, despite removal of the constant regions and the introduction of the linker. The image to the right shows how this modification usually leaves the specificity unaltered.
Chemical biology is a scientific discipline between the fields of chemistry and biology. The discipline involves the application of chemical techniques, analysis, and often small molecules produced through synthetic chemistry, to the study and manipulation of biological systems. In contrast to biochemistry, which involves the study of the chemistry of biomolecules and regulation of biochemical pathways within and between cells, chemical biology deals with chemistry applied to biology.
Aptamers are short sequences of artificial DNA, RNA, XNA, or peptide that bind a specific target molecule, or family of target molecules. They exhibit a range of affinities, with variable levels of off-target binding and are sometimes classified as chemical antibodies. Aptamers and antibodies can be used in many of the same applications, but the nucleic acid-based structure of aptamers, which are mostly oligonucleotides, is very different from the amino acid-based structure of antibodies, which are proteins. This difference can make aptamers a better choice than antibodies for some purposes.
In immunology, epitope mapping is the process of experimentally identifying the binding site, or epitope, of an antibody on its target antigen. Identification and characterization of antibody binding sites aid in the discovery and development of new therapeutics, vaccines, and diagnostics. Epitope characterization can also help elucidate the binding mechanism of an antibody and can strengthen intellectual property (patent) protection. Experimental epitope mapping data can be incorporated into robust algorithms to facilitate in silico prediction of B-cell epitopes based on sequence and/or structural data.
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from Latin ligare, which means 'to bind'. In protein-ligand binding, the ligand is usually a molecule which produces a signal by binding to a site on a target protein. The binding typically results in a change of conformational isomerism (conformation) of the target protein. In DNA-ligand binding studies, the ligand can be a small molecule, ion, or protein which binds to the DNA double helix. The relationship between ligand and binding partner is a function of charge, hydrophobicity, and molecular structure.
A single-domain antibody (sdAb), also known as a NANOBODY®, is an antibody fragment consisting of a single monomeric variable antibody domain. Like a whole antibody, it is able to bind selectively to a specific antigen. With a molecular weight of only 12–15 kDa, single-domain antibodies are much smaller than common antibodies which are composed of two heavy protein chains and two light chains, and even smaller than Fab fragments and single-chain variable fragments.
Protein tags are peptide sequences genetically grafted onto a recombinant protein. Tags are attached to proteins for various purposes. They can be added to either end of the target protein, so they are either C-terminus or N-terminus specific or are both C-terminus and N-terminus specific. Some tags are also inserted at sites within the protein of interest; they are known as internal tags.
In biology, cell signaling or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellular life in prokaryotes and eukaryotes. Signals that originate from outside a cell can be physical agents like mechanical pressure, voltage, temperature, light, or chemical signals. Cell signaling can occur over short or long distances, and as a result can be classified as autocrine, juxtacrine, intracrine, paracrine, or endocrine. Signaling molecules can be synthesized from various biosynthetic pathways and released through passive or active transports, or even from cell damage.
Directed evolution (DE) is a method used in protein engineering that mimics the process of natural selection to steer proteins or nucleic acids toward a user-defined goal. It consists of subjecting a gene to iterative rounds of mutagenesis, selection and amplification. It can be performed in vivo, or in vitro. Directed evolution is used both for protein engineering as an alternative to rationally designing modified proteins, as well as for experimental evolution studies of fundamental evolutionary principles in a controlled, laboratory environment.
Heterotrimeric G protein, also sometimes referred to as the "large" G proteins are membrane-associated G proteins that form a heterotrimeric complex. The biggest non-structural difference between heterotrimeric and monomeric G protein is that heterotrimeric proteins bind to their cell-surface receptors, called G protein-coupled receptors, directly. These G proteins are made up of alpha (α), beta (β) and gamma (γ) subunits. The alpha subunit is attached to either a GTP or GDP, which serves as an on-off switch for the activation of G-protein.
William (Bill) DeGrado is a professor at the University of California, San Francisco, where he is the Toby Herfindal Presidential Professor of Entrepreneurship and Innovation in the Department of Pharmaceutical Chemistry. As an early pioneer of protein design, he coined the term de novo protein design. He is also active in discovery of small molecule drugs for a variety of human diseases. He is a member of the U.S. National Academy of Sciences (1999), American Academy of Arts & Sciences (1997) and National Academy of Inventors. He also is a scientific cofounder of Pliant therapeutics.
Kim D. Janda is an American chemist who studies on medicinal chemistry, molecular biology, immunology and neuropharmacology.
Affibody molecules are small, robust proteins engineered to bind to a large number of target proteins or peptides with high affinity, imitating monoclonal antibodies, and are therefore a member of the family of antibody mimetics. Affibody molecules are used in biochemical research and are being developed as potential new biopharmaceutical drugs. These molecules can be used for molecular recognition in diagnostic and therapeutic applications.
Chemically Induced Dimerization (CID) is a biological mechanism in which two proteins bind only in the presence of a certain small molecule, enzyme or other dimerizing agent. Genetically engineered CID systems are used in biological research to control protein localization, to manipulate signalling pathways and to induce protein activation.
Wendell Lim is an American biochemist who is the Byer's Distinguished Professor of Cellular and Molecular Pharmacology at the University of California, San Francisco. He is the director of the UCSF Cell Design Institute. He earned his A.B. in chemistry from Harvard University working with Jeremy Knowles on enzyme evolutionary optimization. He obtained his Ph.D in biochemistry and biophysics from Massachusetts Institute of Technology under the guidance of Bob Sauer using genetic and biophysical approaches to understand the role of hydrophobic core interactions in protein folding. He then did his postdoctoral work with Frederic Richards at Yale University on the structure of protein interaction domains. Lim's work has focused on cell signaling, synthetic biology, and cell engineering, particularly in immune cells.
Affimer molecules are small proteins that bind to target proteins with affinity in the nanomolar range. These engineered non-antibody binding proteins are designed to mimic the molecular recognition characteristics of monoclonal antibodies in different applications. These affinity reagents have been optimized to increase their stability, make them tolerant to a range of temperatures and pH, reduce their size, and to increase their expression in E.coli and mammalian cells.
Recombinant antibodies are antibody fragments produced by using recombinant antibody coding genes. They mostly consist of a heavy and light chain of the variable region of immunoglobulin. Recombinant antibodies have many advantages in both medical and research applications, which make them a popular subject of exploration and new production against specific targets. The most commonly used form is the single chain variable fragment (scFv), which has shown the most promising traits exploitable in human medicine and research. In contrast to monoclonal antibodies produced by hybridoma technology, which may lose the capacity to produce the desired antibody over time or the antibody may undergo unwanted changes, which affect its functionality, recombinant antibodies produced in phage display maintain high standard of specificity and low immunogenicity.